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Szabó IL, Emri G, Ladányi A, Tímár J. Clinical Applications of the Molecular Landscape of Melanoma: Integration of Research into Diagnostic and Therapeutic Strategies. Cancers (Basel) 2025; 17:1422. [PMID: 40361349 PMCID: PMC12071057 DOI: 10.3390/cancers17091422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2025] [Revised: 04/21/2025] [Accepted: 04/22/2025] [Indexed: 05/15/2025] Open
Abstract
The molecular landscape of cutaneous melanoma is complex and heterogeneous, and a deeper understanding of the genesis and progression of the tumor driven by genetic alterations is essential for the development of effective diagnostic and therapeutic strategies. Molecular diagnostics and the use of biomarkers are increasingly playing a role in treatment decisions. However, further research is urgently needed to elucidate the relationships between complex genetic alterations and the effectiveness of target therapies (although BRAF mutation is still the only targeted genetic alteration). Further research is required to exploit other targetable genetic alterations such as NRAS, KIT or rare mutations. Treatment guidelines for cutaneous melanoma are continually evolving based on data from recent and ongoing clinical trials. These advancements reflect changes mainly in the optimal timing of systemic therapy and the choice of combination therapies increasingly tailored to molecular profiles of individual tumors. Mono- or combination immunotherapies demonstrated unprecedented success of melanoma treatment; still, there is room for improvement: though several factors of primary or acquired resistance are known, they are not part of patient management as biomarkers. The novel developments of cancer vaccines to treat melanoma (melanoma-marker-based or personalized neoantigen-based) are encouraging; introduction of them into clinical practice without proper biomarkers would be the same mistake made in the case of first-generation immunotherapies.
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Affiliation(s)
- Imre Lőrinc Szabó
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (I.L.S.); (G.E.)
- HUN-REN-UD Allergology Research Group, University of Debrecen, 4032 Debrecen, Hungary
| | - Gabriella Emri
- Department of Dermatology, MTA Centre of Excellence, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (I.L.S.); (G.E.)
- HUN-REN-UD Allergology Research Group, University of Debrecen, 4032 Debrecen, Hungary
| | - Andrea Ladányi
- Department of Surgical and Molecular Pathology, National Institute of Oncology, 1122 Budapest, Hungary;
- National Tumor Biology Laboratory, National Institute of Oncology, 1122 Budapest, Hungary
| | - József Tímár
- Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, 1091 Budapest, Hungary
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Feng X, Zeng R, Lyu M, Chen X, Xu Z, Hu Y, Bao Z, Sun X, Zhao J, Zhou L, Zhou J, Gao B, Dong L, Xiang Y. Clinical and molecular characteristics, therapeutic strategies, and prognosis of non-small cell lung cancer patients harboring primary and acquired BRAF mutations. Front Oncol 2025; 15:1514653. [PMID: 40242250 PMCID: PMC11999832 DOI: 10.3389/fonc.2025.1514653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 03/14/2025] [Indexed: 04/18/2025] Open
Abstract
Background The differences in clinical characteristics and treatment prognosis in NSCLC patients harboring primary and acquired BRAF mutations are still poorly understood. Methods From Oct 2017 to Dec 2023, 10, 211 lung cancer patients at Shanghai Ruijin Hospital were reviewed. 88 primary and 15 acquired BRAF-mutated NSCLC patients resistant to EGFR TKIs were included in the study. Results Primary BRAF-mutated patients preferentially occurred in the elderly (median age: 67 vs 61, p=0.015), males (53.4% vs 26.7%, p=0.056), former/current smokers (36.5% vs 6.7%, p=0.033), non-adenocarcinoma (11.4% vs 0%, P=0.351) compared to acquired BRAF-mutated patients. Significant differences in gender (33.3% vs 62.3%, p=0.012), smoking history (22.2% vs 43.1%, p=0.063), and adenocarcinomas (100% vs 83.6%, p=0.028) were observed between primary BRAF/EGFR co-mutated and non-co-mutated groups. While primary and acquired BRAF/EGFR co-mutated patients had similar clinical characteristics, with EGFR mutations being the most common coexisting oncogene (30.7% and 93.3%). The genotype of EGFR mutations differed, with acquired BRAF-mutated cases showing more complexity and a higher rate of dual EGFR mutations (35.7%) compared to primary cases. For primary BRAF/EGFR co-mutated patients, no matter what kinds of therapies, the EGFR 19del patients had a better prognosis than non-19del patients, and the first line mPFS was NR and 9.0 months (95% CI: 7.7-10.3 months) (p=0.0062), respectively. Dabrafenib and trametinib plus 3rd EGFR TKIs improved the prognosis of primary BRAF/EGFR non-19del co-mutated patients, achieving ORR and mPFS of 100% (3/3) and 12 months. For acquired co-mutated patients, the mPFS for 5 patients was 8.6 months (95% CI: 5.4-11.8 months). No new safety concerns and > grade 3 AEs were noted. Conclusion Together, our study demonstrates that primary and acquired BRAF-mutant patients show distinct differences in some clinical and molecular characteristics, but acquired BRAF/EGFR co-mutated and primary BRAF/EGFR non-19del co-mutated patients may both respond to triple-targeted therapy.
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Affiliation(s)
- Xiangran Feng
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ran Zeng
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mengchen Lyu
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoyan Chen
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ziwei Xu
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yue Hu
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhiyao Bao
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Emergency Prevention, Diagnosis, and Treatment of Respiratory Infectious Diseases, Shanghai, China
| | - Xianwen Sun
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Emergency Prevention, Diagnosis, and Treatment of Respiratory Infectious Diseases, Shanghai, China
| | - Jingya Zhao
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Emergency Prevention, Diagnosis, and Treatment of Respiratory Infectious Diseases, Shanghai, China
| | - Ling Zhou
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Emergency Prevention, Diagnosis, and Treatment of Respiratory Infectious Diseases, Shanghai, China
| | - Jun Zhou
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Emergency Prevention, Diagnosis, and Treatment of Respiratory Infectious Diseases, Shanghai, China
| | - Beili Gao
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Emergency Prevention, Diagnosis, and Treatment of Respiratory Infectious Diseases, Shanghai, China
| | - Lei Dong
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yi Xiang
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Emergency Prevention, Diagnosis, and Treatment of Respiratory Infectious Diseases, Shanghai, China
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Gupta PK, Li LZ, Singh DK, Nova S, Arias-Mendoza F, Orlovskiy S, Chawla S, Nelson DS, Farwell MD, Nath K. MRS and Optical Imaging Studies of Therapeutic Response to Combination Therapy Targeting BRAF/MEK in Murine Melanomas. Acad Radiol 2025:S1076-6332(25)00090-X. [PMID: 39984334 DOI: 10.1016/j.acra.2025.01.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 01/24/2025] [Accepted: 01/26/2025] [Indexed: 02/23/2025]
Abstract
RATIONALE AND OBJECTIVES Melanoma, an aggressive skin cancer, often harbors BRAFV600E mutations driving tumor progression via the mitogen-activated protein kinase (MAPK) pathway. While targeted therapies like BRAF (dabrafenib) and MEK (trametinib) inhibitors have improved outcomes, resistance linked to metabolic reprogramming remains a challenge. This study investigates metabolic changes induced by dual BRAF/MEK inhibition in a BRAFV600E-mutant murine melanoma model using magnetic resonance spectroscopy (MRS), optical redox imaging (ORI), and biochemical assays. We aim to identify metabolic biomarkers for predicting therapeutic response or resistance. MATERIALS AND METHODS YUMM1.7 murine melanoma cells and tumored mice were treated with dabrafenib and trametinib. ORI assessed mitochondrial redox status by measuring reduced nicotinamide adenine dinucleotide (NADH), oxidized flavoproteins (Fp), and the redox ratio (Fp/(NADH+Fp)) in vitro. Glucose consumption and lactate production were analyzed using a YSI Biochemical Analyzer. In vivo metabolic changes were monitored via ¹H and ³¹P MRS, evaluating lactate, alanine, pH, βNTP/Pi, and total NAD(P)(H), which represents combined oxidized nicotinamide adenine dinucleotide (NAD+), NADH, and reduced nicotinamide adenine dinucleotide phosphate (NADPH). RESULTS Under the combined therapeutic regimen of dabrafenib and trametinib, YUMM1.7 murine melanoma cells exhibited significant inhibition of lactate generation, non-significant reduction of glucose utilization, decreased intracellular levels of NADH and total NAD(P)(H), and more oxidized redox status in vitro, which can be interpreted as inhibition of the Warburg effect and improved OXPHOS efficiency by targeting BRAF/MEK signaling activities. Furthermore, YUMM1.7 mouse tumors demonstrated less tissue acidification and improved bioenergetics (βNTP/Pi), in agreement with the in vitro data. CONCLUSION MRS, ORI, and biochemical assays identified critical metabolic changes, highlighting potential biomarkers and supporting the integration of metabolic inhibitors with MAPK-targeted therapies to improve clinical outcomes.
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Affiliation(s)
- Pradeep Kumar Gupta
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (P.K.G., L.Z.L., D.K.S., S.N., F.A.M., S.O., S.C., D.S.N., M.D.F., K.N.)
| | - Lin Z Li
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (P.K.G., L.Z.L., D.K.S., S.N., F.A.M., S.O., S.C., D.S.N., M.D.F., K.N.); Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (L.Z.L., K.N.); Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania (L.Z.L., K.N.)
| | - Dinesh Kumar Singh
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (P.K.G., L.Z.L., D.K.S., S.N., F.A.M., S.O., S.C., D.S.N., M.D.F., K.N.)
| | - Skyler Nova
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (P.K.G., L.Z.L., D.K.S., S.N., F.A.M., S.O., S.C., D.S.N., M.D.F., K.N.)
| | - Fernando Arias-Mendoza
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (P.K.G., L.Z.L., D.K.S., S.N., F.A.M., S.O., S.C., D.S.N., M.D.F., K.N.); Advanced Imaging Research, Inc. Cleveland, Ohio (F.A.M.)
| | - Stepan Orlovskiy
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (P.K.G., L.Z.L., D.K.S., S.N., F.A.M., S.O., S.C., D.S.N., M.D.F., K.N.)
| | - Sanjeev Chawla
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (P.K.G., L.Z.L., D.K.S., S.N., F.A.M., S.O., S.C., D.S.N., M.D.F., K.N.)
| | - David S Nelson
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (P.K.G., L.Z.L., D.K.S., S.N., F.A.M., S.O., S.C., D.S.N., M.D.F., K.N.)
| | - Michael D Farwell
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (P.K.G., L.Z.L., D.K.S., S.N., F.A.M., S.O., S.C., D.S.N., M.D.F., K.N.)
| | - Kavindra Nath
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (P.K.G., L.Z.L., D.K.S., S.N., F.A.M., S.O., S.C., D.S.N., M.D.F., K.N.); Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania (L.Z.L., K.N.); Institute of Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania (L.Z.L., K.N.).
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Luo X, Duan Y, He J, Huang C, Liu J, Liu Y, Xu M, Dai Q, Yang Z. Dihydrotanshinone I enhanced BRAF mutant melanoma treatment efficacy by inhibiting the STAT3/SOX2 signaling pathway. Front Oncol 2025; 15:1429018. [PMID: 39944829 PMCID: PMC11813777 DOI: 10.3389/fonc.2025.1429018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 01/13/2025] [Indexed: 04/02/2025] Open
Abstract
BACKGROUND The Food and Drug Administration has approved the Serine/threonine-protein kinase B-raf (BRAF) inhibitor and Mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor combo as the first-line treatment for individuals with metastatic melanoma, although the majority of these patients exhibit primary or secondary drug resistance in the clinic. Dihydrotanshinone I (DHT) is a lipophilic compound extracted from the root of Salvia miltiorrhiza that has been linked to multiple antitumor activities. In this study, we investigated the effect of dihydrotanshinone I on the MAPK pathway inhibitor resistance of BRAF mutant malignant melanoma. METHOD After treating A375, A375R, and A2058 cells with DHT or a combination of DHT and BRAF/MEK inhibitors, WB and Real-Time RT-qPCR were used to confirm the activation of the MAPK and STAT3/SOX2 pathways. CCK-8 was used to assess cell viability, while flow cytometry was used to identify apoptosis. In addition, mice were inoculated with A375 cells to establish a model of tumour formation, and various drug groups and treatment models were utilized. The diameter and weight of tumours in each group were then measured, and IHC and HE staining were used to assess the expression of two pathways and cytotoxicity, respectively. RESULTS This study found that DHT directly interacts with STAT3 protein and it can stop the feedback activation of the STAT3/SOX2 pathway caused by the use of MAPK pathway inhibitors. In addition, the combination of DHT and BRAF/MEK inhibitors can inhibit the proliferation and growth of BRAF mutant melanoma cells and primary and secondary drug-resistant cells. Finally, we proved that the combined therapy of DHT and BRAF/MEK inhibitors is reliable and effective at animal and cell levels. CONCLUSION In BRAF mutant melanoma cells, DHT suppresses the STAT3/SOX2 signaling pathway. Combining DHT, BRAF inhibitors, and MEK inhibitors can help treat treatment-resistant BRAF mutant melanoma cells. Experimental results both in vitro and in vivo have shown that the combination of DHT and an inhibitor of the MAPK pathway is safer and more successful than using an inhibitor of the MAPK pathway alone when treating BRAF mutant melanoma.
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Affiliation(s)
- Xing Luo
- Department of Pathology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yi Duan
- Department of Pathology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Jinwei He
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China
| | - CongGai Huang
- Department of Pathology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Jun Liu
- Department of Pathology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yifan Liu
- School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China
| | - Mengdei Xu
- Clinical School of Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Qiong Dai
- Department of Human Anatomy, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan, China
| | - Zhihui Yang
- Department of Pathology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
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Goodwin CR, De la Garza Ramos R, Bettegowda C, Barzilai O, Shreyaskumar P, Fehlings MG, Laufer I, Sahgal A, Rhines LD, Reynolds JJ, Lazary A, Gasbarrini A, Dea N, Verlaan JJ, Sullivan PZ, Gokaslan ZL, Fisher CG, Boriani S, Shin JH, Hornicek FJ, Weber MH, Goodwin ML, Charest-Morin R. Overview of Molecular Prognostication for Common Solid Tumor Histologies - What the Surgeon Should Know. Global Spine J 2025; 15:6S-15S. [PMID: 39801124 PMCID: PMC11726510 DOI: 10.1177/21925682241250327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2025] Open
Abstract
STUDY DESIGN Narrative Literature review. OBJECTIVE To provide a general overview of important molecular markers and targeted therapies for the most common neoplasms (lung, breast, prostate and melanoma) that metastasize to the spine and offer guidance on how to best incorporate them in the clinical setting. METHODS A narrative review of the literature was performed using PubMed, Google Scholar, Medline databases, as well as the histology-specific National Comprehensive Cancer Network guidelines to identify relevant articles limited to the English language. Relevant articles were reviewed for commonly described molecular mutations or targeted therapeutics, as well as associated clinical outcomes, and surgery-related risks. RESULTS Molecular markers and targeted therapies have dramatically improved the survival of cancer patients. The increasing importance of prognostic molecular markers and targeted therapies provides rationale for their incorporation into clinical decision-making for patients diagnosed with metastatic spine disease. In this review, we discuss the molecular markers/mutations and targeted therapies associated with the most common malignancies that metastasize to the spine and provide a framework that the surgeon can utilize when evaluating patients for potential intervention. Finally, we provide case examples that highlight the importance of molecular prognostication and therapies in surgical decision-making. CONCLUSION An integrated understanding of the implications of surgery, radiation, molecular markers and targeted therapies that guide prognostication and treatment is warranted in order to achieve the most favorable outcomes for patients with metastatic spine disease.
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Affiliation(s)
- C Rory Goodwin
- Department of Neurosurgery, Spine Division, Duke University, Durham, NC, USA
| | - Rafael De la Garza Ramos
- Department of Neurological Surgery, Montefiore Medical Center Albert Einstein College of Medicine, New York, NY, USA
| | - Chetan Bettegowda
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ori Barzilai
- Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Patel Shreyaskumar
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, University of Texas, Houston, TX, USA
| | - Michael G Fehlings
- Department of Surgery, Division of Neurosurgery and Spine Program, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Ilya Laufer
- Department of Neurological Surgery, New York University Grossman School of Medicine, New York, NY, USA
| | - Arjun Sahgal
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
| | - Laurence D Rhines
- Department of Neurosurgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, University of Texas, Houston, TX, USA
| | | | - Aron Lazary
- National Center for Spinal Disorders, Budapest, Hungary
| | - Alessandro Gasbarrini
- Spine Surgery, University of Bologna, Contract Professor of Orthopedics at PostGraduate School, Bologna, Italy
| | - Nicolas Dea
- Combined Neurosurgical and Orthopedic Spine Program, Department of Orthopedics Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Jorrit-Jan Verlaan
- Department of Orthopaedic Surgery, University Medical Center Utrecht - Utrecht University, Utrecht, The Netherlands
| | - Patricia Zadnik Sullivan
- Department of Neurosurgery, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Ziya L Gokaslan
- Department of Neurosurgery, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Charles G Fisher
- Combined Neurosurgical and Orthopedic Spine Program, Department of Orthopedics Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Stefano Boriani
- Spine Surgery, University of Bologna, Contract Professor of Orthopedics at PostGraduate School, Bologna, Italy
| | - John H Shin
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Francis J Hornicek
- Department of Orthopaedic Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Michael H Weber
- Spine Surgery Program, Department of Surgery, Montreal General Hospital, McGill University Health Center, Montreal, QC, Canada
| | - Matthew L Goodwin
- Department of Orthopaedic Surgery, Washington University in St Louis, St Louis, MO, USA
| | - Raphaële Charest-Morin
- Combined Neurosurgical and Orthopedic Spine Program, Department of Orthopedics Surgery, University of British Columbia, Vancouver, BC, Canada
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Fernandes M, Barcelos D, Carapeto FCL, Cardili L, Comodo AN, Mazloum SF, Marins MM, Mendes AR, Pesquero JB, Landman G. Evaluation of Heterogeneity in the Coding Region of BRAF, MAP2K1, and MAP2K2 Genes in Primary and Metastatic Melanomas. J Cutan Pathol 2024. [PMID: 39588764 DOI: 10.1111/cup.14738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 09/24/2024] [Accepted: 10/07/2024] [Indexed: 11/27/2024]
Abstract
INTRODUCTION The incidence of melanoma has been increasing in recent decades. BRAF mutations appear in 50%-70% of melanomas. The BRAF-targeted therapy increased the disease-free survival of patients with metastatic melanoma, but this response may be short, due to several resistance mechanisms, such as the presence of other subclones with mutations. Evaluation of mutations and heterogeneity in the coding region of the BRAF, MAP2K1, and MAP2K2 genes in primary and metastatic melanomas. PATIENTS AND METHODS Twenty-seven samples of primary and metastatic superficial spreading melanoma (SSM) and acral lentiginous melanoma (ALM) were analyzed for BRAF, MAP2K1, and MAP2K2 mutations using the next-generation sequencing technique. RESULTS In ALM, the mutation rate found was 50% in the BRAF and MAP2K1 genes and 28.6% in MAP2K2. In the SSM, BRAF was mutated in 76.9%, MAP2K1 in 30.8%, and MAP2K2 in 23.2% of the cases. All samples were formed by distinct tumor subclones in the same lesion. Intertumoral heterogeneity was present between primary and metastatic lesions of ALM in BRAF, MAP2K1, and MAP2K2; the cases of SSM were heterogeneous for BRAF and MAP2K1. CONCLUSION We sought to evaluate the mutations in the BRAF, MAP2K1, and MAP2K2 genes, revealing a heterogeneous mutation profile in samples of ALM and SSM.
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Affiliation(s)
- Mariana Fernandes
- Departament of Pathology, Federal University of São Paulo, São Paulo, Brazil
| | - Denise Barcelos
- Departament of Pathology, Federal University of São Paulo, São Paulo, Brazil
| | | | - Leonardo Cardili
- Departament of Pathology, Federal University of São Paulo, São Paulo, Brazil
| | | | | | - Maryana Mara Marins
- Departament of Biophysics, Federal University of São Paulo, São Paulo, Brazil
| | | | - João Bosco Pesquero
- Departament of Biophysics, Federal University of São Paulo, São Paulo, Brazil
| | - Gilles Landman
- Departament of Pathology, Federal University of São Paulo, São Paulo, Brazil
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Pedersen S, Nielsen MØ, Donia M, Svane IM, Zerahn B, Ellebaek E. Real-World Cardiotoxicity in Metastatic Melanoma Patients Treated with Encorafenib and Binimetinib. Cancers (Basel) 2024; 16:2945. [PMID: 39272803 PMCID: PMC11394091 DOI: 10.3390/cancers16172945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 08/16/2024] [Accepted: 08/23/2024] [Indexed: 09/15/2024] Open
Abstract
Modern therapies targeting the BRAF gene mutation in advanced melanoma have significantly improved patient outcomes but pose cardiovascular risks. This retrospective study in Eastern Denmark (2019-2022) assessed 108 melanoma patients treated with encorafenib and binimetinib. Patients were monitored for heart function using multigated acquisition (MUGA) scans. The study defined major cardiotoxicity as a decline in left ventricular ejection fraction (LVEF) by more than 10 percentage points to below 50%, and minor cardiotoxicity as a decrease in LVEF by more than 15 points but remaining above 50%. Results showed that 19 patients (18%) developed minor cardiotoxicity and were asymptomatic, while 7 (6%) experienced major cardiotoxicity, with two requiring intervention. Notably, no significant declines in LVEF were observed after six months of treatment. The study concluded that significant cardiotoxicity occurred in 6% of cases, mostly asymptomatic and reversible, and suggests that monitoring LVEF could potentially be reduced after 6-9 months if no early signs of cardiotoxicity are detected. This provides valuable insights into the cardiac safety of these treatments in real-world settings.
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Affiliation(s)
- Sidsel Pedersen
- Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, 2730 Herlev, Denmark
| | - Marc Østergaard Nielsen
- Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital, Herlev and Gentofte, 2730 Herlev, Denmark
| | - Marco Donia
- Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, 2730 Herlev, Denmark
| | - Inge Marie Svane
- Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, 2730 Herlev, Denmark
| | - Bo Zerahn
- Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital, Herlev and Gentofte, 2730 Herlev, Denmark
| | - Eva Ellebaek
- Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, 2730 Herlev, Denmark
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Bialves TS, Bastos LL, Parra JAA, Moysés MN, Marques E, de Castro Pimenta AM, Quintela FM, Mariano DCB, Carvalho FC, de Melo-Minardi RC, Boyle RT. Interaction of DisBa01 peptide from Bothrops alternatus venom with BRAF melanoma receptors: Modeling and molecular docking. Int J Biol Macromol 2024; 274:133283. [PMID: 38909731 DOI: 10.1016/j.ijbiomac.2024.133283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 06/12/2024] [Accepted: 06/18/2024] [Indexed: 06/25/2024]
Abstract
Metastatic melanoma is highly aggressive and challenging, often leading to a grim prognosis. Its progression is swift, especially when mutations like BRAFV600E continuously activate pathways vital for cell growth and survival. Although several treatments target this mutation, resistance typically emerges over time. In recent decades, research has underscored the potential of snake venoms and peptides as bioactive substances for innovative drugs, including anti-coagulants, anti-microbial, and anti-cancer agents. Leveraging this knowledge, we propose employing a bioinformatics simulation approach to: a) Predict how well a peptide (DisBa01) from Bothrops alternatus snake venom binds to the melanoma receptor BRAFV600E via Molecular Docking. b) Identify the specific peptide binding sites on receptors and analyze their proximity to active receptor sites. c) Evaluate the behavior of resulting complexes through molecular dynamics simulations. d) Assess whether this peptide qualifies as a candidate for anti-melanoma therapy. Our findings reveal that DisBa01 enhances stability in the BRAFV600E melanoma receptor structure by binding to its RGD motif, an interaction absent in the BRAF WT model. Consequently, both docking and molecular dynamics simulations suggest that DisBa01 shows promise as a BRAFV600E inhibitor.
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Affiliation(s)
- Tatiane Senna Bialves
- Graduate Program in Physiological Sciences (PPGCF), Federal University of Rio Grande - FURG, Av. Italy, s/n - km 8 - Carreiros, Rio Grande, Rio Grande do Sul, Brazil.
| | - Luana Luiza Bastos
- Laboratory of Bioinformatics and Systems, Institute of Exact Sciences, Department of Computer Science, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - John Alexanders Amaya Parra
- Graduate Program in Biochemistry and Immunology, Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Maurício Nogueira Moysés
- Graduate Program in Biochemistry and Immunology, Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Edleusa Marques
- Graduate Program in Biochemistry and Immunology, Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Adriano Monteiro de Castro Pimenta
- Graduate Program in Biochemistry and Immunology, Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Fernando Marques Quintela
- Instituto Nacional de Pesquisas do Pantanal- Museu Paraense Emílio Goeldi, Av. Magalhães Barata, 376, Belém, Pará, Brazil
| | - Diego César Batista Mariano
- Laboratory of Bioinformatics and Systems, Institute of Exact Sciences, Department of Computer Science, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Frederico Chaves Carvalho
- Laboratory of Bioinformatics and Systems, Institute of Exact Sciences, Department of Computer Science, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Raquel C de Melo-Minardi
- Laboratory of Bioinformatics and Systems, Institute of Exact Sciences, Department of Computer Science, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Robert Tew Boyle
- Graduate Program in Physiological Sciences (PPGCF), Federal University of Rio Grande - FURG, Av. Italy, s/n - km 8 - Carreiros, Rio Grande, Rio Grande do Sul, Brazil
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9
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Gupta PK, Orlovskiy S, Arias-Mendoza F, Nelson DS, Osborne A, Pickup S, Glickson JD, Nath K. Metabolic Imaging Biomarkers of Response to Signaling Inhibition Therapy in Melanoma. Cancers (Basel) 2024; 16:365. [PMID: 38254853 PMCID: PMC10814512 DOI: 10.3390/cancers16020365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 01/06/2024] [Accepted: 01/10/2024] [Indexed: 01/24/2024] Open
Abstract
Dabrafenib therapy for metastatic melanoma focuses on blocking growth-promoting signals produced by a hyperactive BRAF protein. We report the metabolic differences of four human melanoma cell lines with diverse responses to dabrafenib therapy (30 mg/kg; oral): WM3918 < WM9838BR < WM983B < DB-1. Our goal was to determine if metabolic changes produced by the altered signaling pathway due to BRAF mutations differ in the melanoma models and whether these differences correlate with response to treatment. We assessed metabolic changes in isolated cells using high-resolution proton magnetic resonance spectroscopy (1H MRS) and supplementary biochemical assays. We also noninvasively studied mouse xenografts using proton and phosphorus (1H/31P) MRS. We found consistent changes in lactate and alanine, either in isolated cells or mouse xenografts, correlating with their relative dabrafenib responsiveness. In xenografts, we also observed that a more significant response to dabrafenib correlated with higher bioenergetics (i.e., increased βNTP/Pi). Notably, our noninvasive assessment of the metabolic status of the human melanoma xenografts by 1H/31P MRS demonstrated early metabolite changes preceding therapy response (i.e., tumor shrinkage). Therefore, this noninvasive methodology could be translated to assess in vivo predictive metabolic biomarkers of response in melanoma patients under dabrafenib and probably other signaling inhibition therapies.
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Affiliation(s)
- Pradeep Kumar Gupta
- Molecular Imaging Laboratory, Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.K.G.); (S.O.); (F.A.-M.); (D.S.N.); (A.O.); (S.P.); (J.D.G.)
| | - Stepan Orlovskiy
- Molecular Imaging Laboratory, Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.K.G.); (S.O.); (F.A.-M.); (D.S.N.); (A.O.); (S.P.); (J.D.G.)
| | - Fernando Arias-Mendoza
- Molecular Imaging Laboratory, Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.K.G.); (S.O.); (F.A.-M.); (D.S.N.); (A.O.); (S.P.); (J.D.G.)
- Advanced Imaging Research, Inc., Cleveland, OH 44114, USA
| | - David S. Nelson
- Molecular Imaging Laboratory, Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.K.G.); (S.O.); (F.A.-M.); (D.S.N.); (A.O.); (S.P.); (J.D.G.)
| | - Aria Osborne
- Molecular Imaging Laboratory, Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.K.G.); (S.O.); (F.A.-M.); (D.S.N.); (A.O.); (S.P.); (J.D.G.)
| | - Stephen Pickup
- Molecular Imaging Laboratory, Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.K.G.); (S.O.); (F.A.-M.); (D.S.N.); (A.O.); (S.P.); (J.D.G.)
| | - Jerry D. Glickson
- Molecular Imaging Laboratory, Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.K.G.); (S.O.); (F.A.-M.); (D.S.N.); (A.O.); (S.P.); (J.D.G.)
| | - Kavindra Nath
- Molecular Imaging Laboratory, Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; (P.K.G.); (S.O.); (F.A.-M.); (D.S.N.); (A.O.); (S.P.); (J.D.G.)
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10
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Wang P, Laster K, Jia X, Dong Z, Liu K. Targeting CRAF kinase in anti-cancer therapy: progress and opportunities. Mol Cancer 2023; 22:208. [PMID: 38111008 PMCID: PMC10726672 DOI: 10.1186/s12943-023-01903-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 11/16/2023] [Indexed: 12/20/2023] Open
Abstract
The RAS/mitogen-activated protein kinase (MAPK) signaling cascade is commonly dysregulated in human malignancies by processes driven by RAS or RAF oncogenes. Among the members of the RAF kinase family, CRAF plays an important role in the RAS-MAPK signaling pathway, as well as in the progression of cancer. Recent research has provided evidence implicating the role of CRAF in the physiological regulation and the resistance to BRAF inhibitors through MAPK-dependent and MAPK-independent mechanisms. Nevertheless, the effectiveness of solely targeting CRAF kinase activity remains controversial. Moreover, the kinase-independent function of CRAF may be essential for lung cancers with KRAS mutations. It is imperative to develop strategies to enhance efficacy and minimize toxicity in tumors driven by RAS or RAF oncogenes. The review investigates CRAF alterations observed in cancers and unravels the distinct roles of CRAF in cancers propelled by diverse oncogenes. This review also seeks to summarize CRAF-interacting proteins and delineate CRAF's regulation across various cancer hallmarks. Additionally, we discuss recent advances in pan-RAF inhibitors and their combination with other therapeutic approaches to improve treatment outcomes and minimize adverse effects in patients with RAF/RAS-mutant tumors. By providing a comprehensive understanding of the multifaceted role of CRAF in cancers and highlighting the latest developments in RAF inhibitor therapies, we endeavor to identify synergistic targets and elucidate resistance pathways, setting the stage for more robust and safer combination strategies for cancer treatment.
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Affiliation(s)
- Penglei Wang
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
- Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, 450052, Henan, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | - Kyle Laster
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | - Xuechao Jia
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China
- Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, 450052, Henan, China
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China
| | - Zigang Dong
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.
- Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, 450052, Henan, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China.
- Department of Pathophysiology, School of Basic Medical Sciences, China-US (Henan) Hormel Cancer Institute, AMS, College of Medicine, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan, China.
| | - Kangdong Liu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450000, China.
- Tianjian Laboratory for Advanced Biomedical Sciences, Zhengzhou, 450052, Henan, China.
- China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China.
- Department of Pathophysiology, School of Basic Medical Sciences, China-US (Henan) Hormel Cancer Institute, AMS, College of Medicine, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, Henan, China.
- Basic Medicine Sciences Research Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China.
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, 450000, Henan, China.
- Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, 450000, Henan, China.
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11
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Bahar ME, Kim HJ, Kim DR. Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies. Signal Transduct Target Ther 2023; 8:455. [PMID: 38105263 PMCID: PMC10725898 DOI: 10.1038/s41392-023-01705-z] [Citation(s) in RCA: 203] [Impact Index Per Article: 101.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 11/03/2023] [Accepted: 11/12/2023] [Indexed: 12/19/2023] Open
Abstract
Metastatic dissemination of solid tumors, a leading cause of cancer-related mortality, underscores the urgent need for enhanced insights into the molecular and cellular mechanisms underlying metastasis, chemoresistance, and the mechanistic backgrounds of individuals whose cancers are prone to migration. The most prevalent signaling cascade governed by multi-kinase inhibitors is the mitogen-activated protein kinase (MAPK) pathway, encompassing the RAS-RAF-MAPK kinase (MEK)-extracellular signal-related kinase (ERK) pathway. RAF kinase is a primary mediator of the MAPK pathway, responsible for the sequential activation of downstream targets, such as MEK and the transcription factor ERK, which control numerous cellular and physiological processes, including organism development, cell cycle control, cell proliferation and differentiation, cell survival, and death. Defects in this signaling cascade are associated with diseases such as cancer. RAF inhibitors (RAFi) combined with MEK blockers represent an FDA-approved therapeutic strategy for numerous RAF-mutant cancers, including melanoma, non-small cell lung carcinoma, and thyroid cancer. However, the development of therapy resistance by cancer cells remains an important barrier. Autophagy, an intracellular lysosome-dependent catabolic recycling process, plays a critical role in the development of RAFi resistance in cancer. Thus, targeting RAF and autophagy could be novel treatment strategies for RAF-mutant cancers. In this review, we delve deeper into the mechanistic insights surrounding RAF kinase signaling in tumorigenesis and RAFi-resistance. Furthermore, we explore and discuss the ongoing development of next-generation RAF inhibitors with enhanced therapeutic profiles. Additionally, this review sheds light on the functional interplay between RAF-targeted therapies and autophagy in cancer.
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Affiliation(s)
- Md Entaz Bahar
- Department of Biochemistry and Convergence Medical Sciences and Institute of Medical Science, Gyeongsang National University, College of Medicine, Jinju, South Korea
| | - Hyun Joon Kim
- Department of Anatomy and Convergence Medical Sciences and Institute of Medical Science, Gyeongsang National University, College of Medicine, Jinju, South Korea
| | - Deok Ryong Kim
- Department of Biochemistry and Convergence Medical Sciences and Institute of Medical Science, Gyeongsang National University, College of Medicine, Jinju, South Korea.
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12
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Shen C, Huang Z, Chen X, Wang Z, Zhou J, Wang Z, Liu D, Li C, Zhao T, Zhang Y, Xu S, Zhou W, Peng W. Rapid ultra-sensitive nucleic acid detection using plasmonic fiber-optic spectral combs and gold nanoparticle-tagged targets. Biosens Bioelectron 2023; 242:115719. [PMID: 37797532 DOI: 10.1016/j.bios.2023.115719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 08/24/2023] [Accepted: 09/28/2023] [Indexed: 10/07/2023]
Abstract
Nucleic acid (NA) is a widely-used biomarker for viruses. Accurate quantification of NA can provide a reliable basis for point-of-care diagnosis and treatment. Here, we propose a tilted fiber Bragg grating (TFBG)-based plasmonic fiber-optic spectral comb for fast response and ultralow limit NA detection. The TFBG is coated with a gold film which enables excitation of surface plasmon resonance (SPR), and single-stranded probe NAs with known base sequences are assembled on the gold film. To enhance sensitivity of refractive index (RI) for sensing a chosen combination of probe and target NAs around the TFBG surface, gold nanoparticles (AuNPs) are bonded to the target NA molecules as "RI-labels". The NA combination-induced aggregation of AuNPs induces significant spectral responses in the TFBG that would be below the detection threshold for the NAs in the absence of the AuNPs. The proposed TFBG-SPR NA sensor shows a fast response time of 30 s and an ultra-wide NA detection range from 1 × 10-18 mol/L to 1 × 10-7 mol/L. In the NA concentration range of 1 × 10-12 mol/L (1 pM) to 105 pM, an ultra-high sensitivity of 1.534 dB/lg(pM) is obtained. The sensor achieves an ultra-low limit of detection down to 1.0 × 10-18 mol/L (1 aM), which is more than an order of magnitude lower than the previous reports. The proposed sensor not only shows potentials in practical applications of NA detection, but also provides a new way for TFBG-SPR biochemical sensors to achieve higher RI sensitivity.
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Affiliation(s)
- Changyu Shen
- College of Optical and Electronic Technology, China Jiliang University, Hangzhou, Zhejiang, 310018, China.
| | - Zhenlin Huang
- College of Optical and Electronic Technology, China Jiliang University, Hangzhou, Zhejiang, 310018, China
| | - Xiaoman Chen
- College of Optical and Electronic Technology, China Jiliang University, Hangzhou, Zhejiang, 310018, China
| | - Zhihao Wang
- College of Optical and Electronic Technology, China Jiliang University, Hangzhou, Zhejiang, 310018, China
| | - Jun Zhou
- College of Optical and Electronic Technology, China Jiliang University, Hangzhou, Zhejiang, 310018, China
| | - Zhaokun Wang
- College of Optical and Electronic Technology, China Jiliang University, Hangzhou, Zhejiang, 310018, China
| | - Dejun Liu
- Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education/Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen, 518060, China
| | - Chenxia Li
- College of Optical and Electronic Technology, China Jiliang University, Hangzhou, Zhejiang, 310018, China
| | - Tianqi Zhao
- College of Optical and Electronic Technology, China Jiliang University, Hangzhou, Zhejiang, 310018, China
| | - Yang Zhang
- School of Physics, Dalian University of Technology, Dalian, Liaoning, 116024, China
| | - Shiqing Xu
- College of Optical and Electronic Technology, China Jiliang University, Hangzhou, Zhejiang, 310018, China
| | - Wenjun Zhou
- College of Optical and Electronic Technology, China Jiliang University, Hangzhou, Zhejiang, 310018, China
| | - Wei Peng
- School of Physics, Dalian University of Technology, Dalian, Liaoning, 116024, China
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13
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Nakai C, Mimaki S, Matsushima K, Shinozaki E, Yamazaki K, Muro K, Yamaguchi K, Nishina T, Yuki S, Shitara K, Bando H, Suzuki Y, Akagi K, Nomura S, Fujii S, Sugiyama M, Nishida N, Mizokami M, Koh Y, Koshizaka T, Okada H, Abe Y, Ohtsu A, Yoshino T, Tsuchihara K. Regulation of MEK inhibitor selumetinib sensitivity by AKT phosphorylation in the novel BRAF L525R mutant. Int J Clin Oncol 2023; 28:654-663. [PMID: 36856908 PMCID: PMC10119053 DOI: 10.1007/s10147-023-02318-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 02/17/2023] [Indexed: 03/02/2023]
Abstract
BACKGROUND Oncogenic mutations in BRAF genes are found in approximately 5-10% of colorectal cancers. The majority of BRAF mutations are located within exons 11-15 of the catalytic kinase domains, with BRAF V600E accounting for more than 80% of the observed BRAF mutations. Sensitivity to BRAF- and mitogen-activated protein kinase (MEK) inhibitors varies depending on BRAF mutations and tumor cell types. Previously, we newly identified, BRAF L525R-mutation, in the activation segment of the kinase in colorectal cancer patient. Here, we characterized the function of the BRAF L525R mutation. METHODS HEK293 cells harboring a BRAF mutation (V600E or L525R) were first characterized and then treated with cetuximab, dabrafenib, and selumetinib. Cell viability was measured using WST-1 assay and the expression of proteins involved in the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) signaling pathways was evaluated using western blot analysis. RESULTS The MEK inhibitor selumetinib effectively inhibited cell proliferation and ERK phosphorylation in BRAF L525R cells but not in BRAF V600E cells. Further studies revealed that AKT phosphorylation was reduced by selumetinib in BRAF L525R cells but not in BRAF V600E cells or selumetinib-resistant BRAF L525R cells. Moreover, the AKT inhibitor overcame the selumetinib resistance. CONCLUSIONS We established a model system harboring BRAF L525R using HEK293 cells. BRAF L525R constitutively activated ERK. AKT phosphorylation caused sensitivity and resistance to selumetinib. Our results suggest that a comprehensive network analysis may provide insights to identify effective therapies.
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Affiliation(s)
- Chikako Nakai
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- G&G Science Co. Ltd., 4-1-1 Misato, Matsukawamachi, Fukushima, 960-1242, Japan
| | - Sachiyo Mimaki
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Koutatsu Matsushima
- G&G Science Co. Ltd., 4-1-1 Misato, Matsukawamachi, Fukushima, 960-1242, Japan
| | - Eiji Shinozaki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-0063, Japan
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimo-Nagakubo, Nagaizumi-Cho, Sunto, Shizuoka, 411-8777, Japan
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-0063, Japan
| | - Tomohiro Nishina
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Minamiumemotomachi, Matsuyama, Ehime, 791-0245, Japan
| | - Satoshi Yuki
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Hideaki Bando
- Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan
| | - Yutaka Suzuki
- Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan
| | - Kiwamu Akagi
- Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, 818 Komuro, Inami-machi, Kitaadachi, Saitama, 362-0806, Japan
| | - Shogo Nomura
- Biostatistics Division, Center for Research and Administration and Support, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Satoshi Fujii
- Department of Molecular Pathology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
| | - Masaya Sugiyama
- Genome Medical Sciences Project, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan
| | - Nao Nishida
- Genome Medical Sciences Project, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan
| | - Masashi Mizokami
- Genome Medical Sciences Project, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan
| | - Yasuhiro Koh
- Third Department of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan
| | - Takuya Koshizaka
- G&G Science Co. Ltd., 4-1-1 Misato, Matsukawamachi, Fukushima, 960-1242, Japan
| | - Hideki Okada
- G&G Science Co. Ltd., 4-1-1 Misato, Matsukawamachi, Fukushima, 960-1242, Japan
| | - Yukiko Abe
- G&G Science Co. Ltd., 4-1-1 Misato, Matsukawamachi, Fukushima, 960-1242, Japan
| | - Atsushi Ohtsu
- National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Katsuya Tsuchihara
- Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
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14
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Vanni I, Pastorino L, Tanda ET, Andreotti V, Dalmasso B, Solari N, Mascherini M, Cabiddu F, Guadagno A, Coco S, Allavena E, Bruno W, Pietra G, Croce M, Gangemi R, Piana M, Zoppoli G, Ferrando L, Spagnolo F, Queirolo P, Ghiorzo P. Whole-Exome Sequencing and cfDNA Analysis Uncover Genetic Determinants of Melanoma Therapy Response in a Real-World Setting. Int J Mol Sci 2023; 24:4302. [PMID: 36901733 PMCID: PMC10002464 DOI: 10.3390/ijms24054302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 02/16/2023] [Accepted: 02/19/2023] [Indexed: 02/24/2023] Open
Abstract
Although several studies have explored the molecular landscape of metastatic melanoma, the genetic determinants of therapy resistance are still largely unknown. Here, we aimed to determine the contribution of whole-exome sequencing and circulating free DNA (cfDNA) analysis in predicting response to therapy in a consecutive real-world cohort of 36 patients, undergoing fresh tissue biopsy and followed during treatment. Although the underpowered sample size limited statistical analysis, samples from non-responders had higher copy number variations and mutations in melanoma driver genes compared to responders in the BRAF V600+ subset. In the BRAF V600- subset, Tumor Mutational Burden (TMB) was twice that in responders vs. non-responders. Genomic layout revealed commonly known and novel potential intrinsic/acquired resistance driver gene variants. Among these, RAC1, FBXW7, GNAQ mutations, and BRAF/PTEN amplification/deletion were present in 42% and 67% of patients, respectively. Both Loss of Heterozygosity (LOH) load and tumor ploidy were inversely associated with TMB. In immunotherapy-treated patients, samples from responders showed higher TMB and lower LOH and were more frequently diploid compared to non-responders. Secondary germline testing and cfDNA analysis proved their efficacy in finding germline predisposing variants carriers (8.3%) and following dynamic changes during treatment as a surrogate of tissue biopsy, respectively.
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Affiliation(s)
- Irene Vanni
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Lorenza Pastorino
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy
| | - Enrica Teresa Tanda
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy
- Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Virginia Andreotti
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Bruna Dalmasso
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Nicola Solari
- Surgical Oncology, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Matteo Mascherini
- Surgical Clinic Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Francesco Cabiddu
- Anatomic Pathology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Antonio Guadagno
- Anatomic Pathology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Simona Coco
- Lung Cancer Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Eleonora Allavena
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy
| | - William Bruno
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy
| | - Gabriella Pietra
- IRCCS Ospedale Policlinico San Martino, U.O. Immunologia, 16132 Genoa, Italy
- Department of Experimental Medicine (DiMES), University of Genoa, 16132 Genoa, Italy
| | - Michela Croce
- Bioterapie, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Rosaria Gangemi
- Bioterapie, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Michele Piana
- Dipartimento di Matematica (MIDA), University of Genoa, 16132 Genoa, Italy
- Life Science Computational Laboratory (LISCOMP), IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Gabriele Zoppoli
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy
- Clinica di Medicina Interna a Indirizzo Oncologico, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Lorenzo Ferrando
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy
- Clinica di Medicina Interna a Indirizzo Oncologico, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Francesco Spagnolo
- Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
- Dipartimento di Scienze Chirurgiche e Diagnostiche Integrate (DISC), University of Genoa, 16132 Genoa, Italy
| | - Paola Queirolo
- Melanoma, Sarcoma & Rare Tumors Division, European Institute of Oncology (IEO), 20141 Milan, Italy
| | - Paola Ghiorzo
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy
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15
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Battaglini D, Fazzini B, Silva PL, Cruz FF, Ball L, Robba C, Rocco PRM, Pelosi P. Challenges in ARDS Definition, Management, and Identification of Effective Personalized Therapies. J Clin Med 2023; 12:1381. [PMID: 36835919 PMCID: PMC9967510 DOI: 10.3390/jcm12041381] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/07/2023] [Accepted: 02/08/2023] [Indexed: 02/12/2023] Open
Abstract
Over the last decade, the management of acute respiratory distress syndrome (ARDS) has made considerable progress both regarding supportive and pharmacologic therapies. Lung protective mechanical ventilation is the cornerstone of ARDS management. Current recommendations on mechanical ventilation in ARDS include the use of low tidal volume (VT) 4-6 mL/kg of predicted body weight, plateau pressure (PPLAT) < 30 cmH2O, and driving pressure (∆P) < 14 cmH2O. Moreover, positive end-expiratory pressure should be individualized. Recently, variables such as mechanical power and transpulmonary pressure seem promising for limiting ventilator-induced lung injury and optimizing ventilator settings. Rescue therapies such as recruitment maneuvers, vasodilators, prone positioning, extracorporeal membrane oxygenation, and extracorporeal carbon dioxide removal have been considered for patients with severe ARDS. Regarding pharmacotherapies, despite more than 50 years of research, no effective treatment has yet been found. However, the identification of ARDS sub-phenotypes has revealed that some pharmacologic therapies that have failed to provide benefits when considering all patients with ARDS can show beneficial effects when these patients were stratified into specific sub-populations; for example, those with hyperinflammation/hypoinflammation. The aim of this narrative review is to provide an overview on current advances in the management of ARDS from mechanical ventilation to pharmacological treatments, including personalized therapy.
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Affiliation(s)
- Denise Battaglini
- Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience, 16132 Genoa, Italy
| | - Brigitta Fazzini
- Adult Critical Care Unit, Royal London Hospital, Barts Health NHS Trust, Whitechapel, London E1 1BB, UK
| | - Pedro Leme Silva
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
| | - Fernanda Ferreira Cruz
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
| | - Lorenzo Ball
- Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience, 16132 Genoa, Italy
- Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, 15145 Genoa, Italy
| | - Chiara Robba
- Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience, 16132 Genoa, Italy
- Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, 15145 Genoa, Italy
| | - Patricia R. M. Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
| | - Paolo Pelosi
- Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience, 16132 Genoa, Italy
- Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, 15145 Genoa, Italy
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16
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Sørensen AL, Guldmann-Christensen M, Børgesen M, Petersen RK, Flugt K, Duelund JMH, Kyneb MH, Lorenzen J, Pipó-Ollé E, Epistolio S, Riva A, Dazio G, Merlo E, Meyer T, Christensen UB, Frattini M. Detection of BRAF mutations in malignant melanoma and colorectal cancer by SensiScreen® FFPE BRAF qPCR assay. PLoS One 2023; 18:e0281558. [PMID: 36758042 PMCID: PMC9910728 DOI: 10.1371/journal.pone.0281558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 01/26/2023] [Indexed: 02/10/2023] Open
Abstract
Mutations in BRAF exon 15 lead to conformational changes in its activation loops, resulting in constitutively active BRAF proteins which are implicated in the development of several human cancer types. Different BRAF inhibitors have been developed and introduced in clinical practice. Identification of BRAF mutations influences the clinical evaluation, treatment, progression and for that reason a sensitive and specific identification of BRAF mutations is on request from the clinic. Here we present the SensiScreen® FFPE BRAF qPCR Assay that uses a novel real-time PCR-based method for BRAF mutation detection based on PentaBases proprietary DNA analogue technology designed to work on standard real-time PCR instruments. The SensiScreen® FFPE BRAF qPCR Assay displays high sensitivity, specificity, fast and easy-to-use. The SensiScreen® FFPE BRAF qPCR Assay was validated on two different FFPE tumour biopsy cohorts, one cohort included malignant melanoma patients previously analyzed by the Cobas® 4800 BRAF V600 Mutation Test, and one cohort from colorectal cancer patients previously analyzed by mutant-enriched PCR and direct sequencing. All BRAF mutant malignant melanoma patients were confirmed with the SensiScreen® FFPE BRAF qPCR Assay and additional four new mutations in the malignant melanoma cohort were identified. All the previously identified BRAF mutations in the colorectal cancer patients were confirmed, and additional three new mutations not identified with direct sequencing were detected. Also, one new BRAF mutation not previously identified with ME-PCR was found. Furthermore, the SensiScreen® FFPE BRAF qPCR Assay identified the specific change in the amino acid. The SensiScreen® FFPE BRAF qPCR Assay will contribute to a more specific, time and cost saving approach to better identify and characterize mutations in patients affected by cancer, and consequently permits a better BRAF characterization that is fundamental for therapy decision.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Samantha Epistolio
- Institute of Pathology EOC, Ente Ospedaliero Cantonale, Locarno, Switzerland
| | - Alice Riva
- Institute of Pathology EOC, Ente Ospedaliero Cantonale, Locarno, Switzerland
| | - Giulia Dazio
- Institute of Pathology EOC, Ente Ospedaliero Cantonale, Locarno, Switzerland
| | - Elisabetta Merlo
- Institute of Pathology EOC, Ente Ospedaliero Cantonale, Locarno, Switzerland
| | - Tine Meyer
- Department of Pathology, Laboratory of Research and Development, Aarhus University Hospital, Aarhus, Denmark
| | | | - Milo Frattini
- Institute of Pathology EOC, Ente Ospedaliero Cantonale, Locarno, Switzerland
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17
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Vemurafenib and Dabrafenib Downregulates RIPK4 Level. Cancers (Basel) 2023; 15:cancers15030918. [PMID: 36765875 PMCID: PMC9913565 DOI: 10.3390/cancers15030918] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/27/2023] [Accepted: 01/29/2023] [Indexed: 02/04/2023] Open
Abstract
Vemurafenib and dabrafenib are BRAF kinase inhibitors (BRAFi) used for the treatment of patients with melanoma carrying the V600E BRAF mutation. However, melanoma cells develop resistance to both drugs when used as monotherapy. Therefore, mechanisms of drug resistance are investigated, and new molecular targets are sought that could completely inhibit melanoma progression. Since receptor-interacting protein kinase (RIPK4) probably functions as an oncogene in melanoma and its structure is similar to the BRAF protein, we analyzed the impact of vemurafenib and dabrafenib on RIPK4 in melanomas. The in silico study confirmed the high similarity of BRAF kinase domains to the RIPK4 protein at both the sequence and structural levels and suggests that BRAFi could directly bind to RIPK4 even more strongly than to ATP. Furthermore, BRAFi inhibited ERK1/2 activity and lowered RIPK4 protein levels in BRAF-mutated melanoma cells (A375 and WM266.4), while in wild-type BRAF cells (BLM and LoVo), both inhibitors decreased the level of RIPK4 and enhanced ERK1/2 activity. The phosphorylation of phosphatidylethanolamine binding protein 1 (PEBP1)-a suppressor of the BRAF/MEK/ERK pathway-via RIPK4 observed in pancreatic cancer did not occur in melanoma. Neither downregulation nor upregulation of RIPK4 in BRAF- mutated cells affected PEBP1 levels or the BRAF/MEK/ERK pathway. The downregulation of RIPK4 inhibited cell proliferation and the FAK/AKT pathway, and increased BRAFi efficiency in WM266.4 cells. However, the silencing of RIPK4 did not induce apoptosis or necroptosis. Our study suggests that RIPK4 may be an off-target for BRAF inhibitors.
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18
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Mela A, Rdzanek E, Tysarowski A, Sakowicz M, Jaroszyński J, Furtak-Niczyporuk M, Żurek G, Poniatowski ŁA, Jagielska B. The impact of changing the funding model for genetic diagnostics and improved access to personalized medicine in oncology. Expert Rev Pharmacoecon Outcomes Res 2023; 23:43-54. [PMID: 36437684 DOI: 10.1080/14737167.2023.2140139] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
AIM In January 2017, a new funding model for diagnostic genetic testing in cancer was introduced in Poland. OBJECTIVES The aim of this study was to assess the impact of changing the funding model for genetic diagnosis in oncology on improving access to personalized medicine in Poland between 2017 and 2019. METHODS The analysis included data on settlements with the National Health Fund for genetic tests in cancer under a contract of the hospital treatment type and under the contract in the type of separately contracted services between 2017 and 2019. RESULTS The 150,647 diagnostic genetic tests were reported, which were billed to 111,872 patients. The average number of tests per patient was 1.35. One test was billed to 83.5% of patients, 11.2% of patients had two tests billed, and 5.3% had at least three tests billed. The number of services provided under the hospital treatment contract in 2018 doubled compared to the previous year. For separately contracted services, more than threefold increase in genetic testing performed in 2019 compared to 2018 was observed. CONCLUSION our data show that the novel funding model for genetic services introduced in Poland has positive impact on the availability of genetic testing for patients.
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Affiliation(s)
- Aneta Mela
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, Warsaw, Poland
| | - Elżbieta Rdzanek
- Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, Warsaw, Poland
| | - Andrzej Tysarowski
- Department of Pathology and Laboratory Medicine, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland.,Department of Molecular and Translational Oncology, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Magdalena Sakowicz
- Department of Health Services Billing, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Janusz Jaroszyński
- Department of Administrative Procedure, Faculty of Law and Administration, Maria Curie-Skłodowska University of Lublin, Lublin, Poland
| | | | - Grzegorz Żurek
- Department of Biostructure, Wrocław University of Health and Sport Sciences, Wrocław, Poland
| | - Łukasz A Poniatowski
- Department of Neurosurgery, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Beata Jagielska
- President of the Polish Alliance for Personalized Medicine Association; Rafal' Masztak Grochów Hospital Independent Public Healthcare Centre, Warsaw, Poland
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19
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Melanogenesis and the Targeted Therapy of Melanoma. Biomolecules 2022; 12:biom12121874. [PMID: 36551302 PMCID: PMC9775438 DOI: 10.3390/biom12121874] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 11/30/2022] [Accepted: 12/09/2022] [Indexed: 12/15/2022] Open
Abstract
Pigment production is a unique character of melanocytes. Numerous factors are linked with melanin production, including genetics, ultraviolet radiation (UVR) and inflammation. Understanding the mechanism of melanogenesis is crucial to identify new preventive and therapeutic strategies in the treatment of melanoma. Here, we reviewed the current available literatures on the mechanisms of melanogenesis, including the signaling pathways of UVR-induced pigment production, MC1R's central determinant roles and MITF as a master transcriptional regulator in melanogenesis. Moreover, we further highlighted the role of targeting BRAF, NRAS and MC1R in melanoma prevention and treatment. The combination therapeutics of immunotherapy and targeted kinase inhibitors are becoming the newest therapeutic option in advanced melanoma.
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20
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Schulz A, Raetz J, Karitzky PC, Dinter L, Tietze JK, Kolbe I, Käubler T, Renner B, Beissert S, Meier F, Westphal D. Head-to-Head Comparison of BRAF/MEK Inhibitor Combinations Proposes Superiority of Encorafenib Plus Trametinib in Melanoma. Cancers (Basel) 2022; 14:cancers14194930. [PMID: 36230853 PMCID: PMC9564158 DOI: 10.3390/cancers14194930] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 10/05/2022] [Accepted: 10/06/2022] [Indexed: 11/24/2022] Open
Abstract
Simple Summary A decade ago, the diagnosis of metastatic melanoma was mostly a death sentence. This has changed since new therapies became widely available in the clinical setting. In addition to checkpoint inhibitors, targeted therapy with BRAF and MEK inhibitors is standard care for BRAF-mutated melanoma, which accounts for almost half of all melanoma cases. The second largest group of melanoma patients, whose tumors harbor a mutation in the NRAS gene, demonstrates only a limited response to targeted therapy with MEK inhibitors. The aim of this investigation was to directly compare all possible BRAF/MEK inhibitor combinations in addition to the currently applied regimens. The analyzed data suggested that the combination of the BRAF inhibitor encorafenib and the MEK inhibitor trametinib demonstrated the highest anti-tumor activity in both, BRAF- and NRAS-mutated melanoma. This combination is not presently used in patient treatment, and therefore, deserves an opportunity to become part of clinical trials. Abstract BRAFV600 mutations in melanoma are targeted with mutation-specific BRAF inhibitors in combination with MEK inhibitors, which have significantly increased overall survival, but eventually lead to resistance in most cases. Additionally, targeted therapy for patients with NRASmutant melanoma is difficult. Our own studies showed that BRAF inhibitors amplify the effects of MEK inhibitors in NRASmutant melanoma. This study aimed at identifying a BRAF and MEK inhibitor combination with superior anti-tumor activity to the three currently approved combinations. We, thus, assessed anti-proliferative and pro-apoptotic activities of all nine as well as resistance-delaying capabilities of the three approved inhibitor combinations in a head-to-head comparison in vitro. The unconventional combination encorafenib/trametinib displayed the highest activity to suppress proliferation and induce apoptosis, acting in an additive manner in BRAFmutant and in a synergistic manner in NRASmutant melanoma cells. Correlating with current clinical studies of approved inhibitor combinations, encorafenib/binimetinib prolonged the time to resistance most efficiently in BRAFmutant cells. Conversely, NRASmutant cells needed the longest time to establish resistance when treated with dabrafenib/trametinib. Together, our data indicate that the most effective combination might not be currently used in clinical settings and could lead to improved overall responses.
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Affiliation(s)
- Alexander Schulz
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität (TU) Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
- National Center for Tumor Diseases (NCT), 01307 Dresden, Germany; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus at TU Dresden, 01307 Dresden, Germany; Helmholtz-Zentrum Dresden–Rossendorf (HZDR), 01328 Dresden, Germany
| | - Jennifer Raetz
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität (TU) Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
| | - Paula C. Karitzky
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität (TU) Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
| | - Lisa Dinter
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität (TU) Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
- National Center for Tumor Diseases (NCT), 01307 Dresden, Germany; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus at TU Dresden, 01307 Dresden, Germany; Helmholtz-Zentrum Dresden–Rossendorf (HZDR), 01328 Dresden, Germany
| | - Julia K. Tietze
- Clinic and Polyclinic for Dermatology and Venereology, University Medical Center Rostock, 18055 Rostock, Germany
| | - Isabell Kolbe
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität (TU) Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
| | - Theresa Käubler
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität (TU) Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
| | - Bertold Renner
- Institute of Clinical Pharmacology, Faculty of Medicine, TU Dresden, 01307 Dresden, Germany
| | - Stefan Beissert
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität (TU) Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
- National Center for Tumor Diseases (NCT), 01307 Dresden, Germany; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus at TU Dresden, 01307 Dresden, Germany; Helmholtz-Zentrum Dresden–Rossendorf (HZDR), 01328 Dresden, Germany
| | - Friedegund Meier
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität (TU) Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
- National Center for Tumor Diseases (NCT), 01307 Dresden, Germany; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus at TU Dresden, 01307 Dresden, Germany; Helmholtz-Zentrum Dresden–Rossendorf (HZDR), 01328 Dresden, Germany
- Skin Cancer Center at the University Cancer Center (UCC) Dresden, University Hospital Carl Gustav Carus at TU Dresden, 01307 Dresden, Germany
| | - Dana Westphal
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität (TU) Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
- National Center for Tumor Diseases (NCT), 01307 Dresden, Germany; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus at TU Dresden, 01307 Dresden, Germany; Helmholtz-Zentrum Dresden–Rossendorf (HZDR), 01328 Dresden, Germany
- Correspondence: ; Tel.: +49-351-458-82274
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21
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Battaglini D, Robba C, Pelosi P, Rocco PRM. Treatment for acute respiratory distress syndrome in adults: A narrative review of phase 2 and 3 trials. Expert Opin Emerg Drugs 2022; 27:187-209. [PMID: 35868654 DOI: 10.1080/14728214.2022.2105833] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Ventilatory management and general supportive care of acute respiratory distress syndrome (ARDS) in the adult population have led to significant clinical improvements, but morbidity and mortality remain high. Pharmacologic strategies acting on the coagulation cascade, inflammation, oxidative stress, and endothelial cell injury have been targeted in the last decade for patients with ARDS, but only a few of these have shown potential benefits with a meaningful clinical response and improved patient outcomes. The lack of availability of specific pharmacologic treatments for ARDS can be attributed to its complex pathophysiology, different risk factors, huge heterogeneity, and difficult classification into specific biological phenotypes and genotypes. AREAS COVERED In this narrative review, we briefly discuss the relevance and current advances in pharmacologic treatments for ARDS in adults and the need for the development of new pharmacological strategies. EXPERT OPINION Identification of ARDS phenotypes, risk factors, heterogeneity, and pathophysiology may help to design clinical trials personalized according to ARDS-specific features, thus hopefully decreasing the rate of failed clinical pharmacologic trials. This concept is still under clinical investigation and needs further development.
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Affiliation(s)
- Denise Battaglini
- Dipartimento di Anestesia e Rianimazione, Policlinico San Martino, IRCCS per l'Oncologia e le Neuroscienze, Largo Rosanna Benzi, 10, 16132, Genoa, Italy
| | - Chiara Robba
- Dipartimento di Anestesia e Rianimazione, Policlinico San Martino, IRCCS per l'Oncologia e le Neuroscienze, Largo Rosanna Benzi, 10, 16132, Genoa, Italy.,Dipartimento di Scienze Chirurgiche e Diagnostiche Integrate, Università degli Studi di Genova, Largo Rosanna Benzi, 10, 16132, Genoa, Italy
| | - Paolo Pelosi
- Dipartimento di Anestesia e Rianimazione, Policlinico San Martino, IRCCS per l'Oncologia e le Neuroscienze, Largo Rosanna Benzi, 10, 16132, Genoa, Italy.,Dipartimento di Scienze Chirurgiche e Diagnostiche Integrate, Università degli Studi di Genova, Largo Rosanna Benzi, 10, 16132, Genoa, Italy
| | - Patricia R M Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Avenida Carlos Chagas Filho, 373, Bloco G1-014, Ilha do Fundão, Rio de Janeiro, RJ 21941-902, Brazil.,COVID-19 Virus Network from Ministry of Science, Technology, and Innovation, Brazilian Council for Scientific and Technological Development, and Foundation Carlos Chagas Filho Research Support of the State of Rio de Janeiro, Rio de Janeiro, Brazil
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22
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Zhang L, Zheng L, Yang Q, Sun J. The Evolution of BRAF Activation in Non-Small-Cell Lung Cancer. Front Oncol 2022; 12:882940. [PMID: 35912223 PMCID: PMC9326470 DOI: 10.3389/fonc.2022.882940] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 05/05/2022] [Indexed: 12/12/2022] Open
Abstract
Non-small-cell lung cancer (NSCLC) is the most common subtype of lung cancer, of which approximate 4% had BRAF activation, with an option for targeted therapy. BRAF activation comprises of V600 and non-V600 mutations, fusion, rearrangement, in-frame deletions, insertions, and co-mutations. In addition, BRAF primary activation and secondary activation presents with different biological phenotypes, medical senses and subsequent treatments. BRAF primary activation plays a critical role in proliferation and metastasis as a driver gene of NSCLC, while secondary activation mediates acquired resistance to other targeted therapy, especially for epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI). Treatment options for different activation of BRAF are diverse. Targeted therapy, especially two-drug combination therapy, is an important option. Besides, immune checkpoint inhibitors (ICIs) would be another option since BRAF activation would be a positive biomarker of tumor response of ICIs therapy. To date, no high level evidences support targeted therapy or immunotherapy as prioritized recommendation. After targeted therapy, the evolution of BRAF includes the activation of the upstream, downstream and bypass pathways of BRAF. In this review, therapeutic modalities and post-therapeutic evolutionary pathways of BRAF are discussed, and future research directions are also provided.
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Affiliation(s)
- Longyao Zhang
- Cancer Institute, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Linpeng Zheng
- Cancer Institute, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Qiao Yang
- Department of Ultrasound, The 941Hospital of the Chinese People's Liberation Army (PLA) Joint Logistic Support Force, Xining, China
| | - Jianguo Sun
- Cancer Institute, Xinqiao Hospital, Army Medical University, Chongqing, China
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23
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Tune BXJ, Sim MS, Poh CL, Guad RM, Woon CK, Hazarika I, Das A, Gopinath SCB, Rajan M, Sekar M, Subramaniyan V, Fuloria NK, Fuloria S, Batumalaie K, Wu YS. Matrix Metalloproteinases in Chemoresistance: Regulatory Roles, Molecular Interactions, and Potential Inhibitors. JOURNAL OF ONCOLOGY 2022; 2022:3249766. [PMID: 35586209 PMCID: PMC9110224 DOI: 10.1155/2022/3249766] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 04/11/2022] [Accepted: 04/19/2022] [Indexed: 02/08/2023]
Abstract
Cancer is one of the major causes of death worldwide. Its treatments usually fail when the tumor has become malignant and metastasized. Metastasis is a key source of cancer recurrence, which often leads to resistance towards chemotherapeutic agents. Hence, most cancer-related deaths are linked to the occurrence of chemoresistance. Although chemoresistance can emerge through a multitude of mechanisms, chemoresistance and metastasis share a similar pathway, which is an epithelial-to-mesenchymal transition (EMT). Matrix metalloproteinases (MMPs), a class of zinc and calcium-chelated enzymes, are found to be key players in driving cancer migration and metastasis through EMT induction. The aim of this review is to discuss the regulatory roles and associated molecular mechanisms of specific MMPs in regulating chemoresistance, particularly EMT initiation and resistance to apoptosis. A brief presentation on their potential diagnostic and prognostic values was also deciphered. It also aimed to describe existing MMP inhibitors and the potential of utilizing other strategies to inhibit MMPs to reduce chemoresistance, such as upstream inhibition of MMP expressions and MMP-responsive nanomaterials to deliver drugs as well as epigenetic regulations. Hence, manipulation of MMP expression can be a powerful tool to aid in treating patients with chemo-resistant cancers. However, much still needs to be done to bring the solution from bench to bedside.
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Affiliation(s)
- Bernadette Xin Jie Tune
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Maw Shin Sim
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Chit Laa Poh
- Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, Selangor 47500, Malaysia
| | - Rhanye Mac Guad
- Department of Biomedical Science and Therapeutics, Faculty of Medicine and Health Science, Universiti Malaysia Sabah, Kota Kinabalu, 88400 Sabah, Malaysia
| | - Choy Ker Woon
- Department of Anatomy, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, 47000 Selangor, Malaysia
| | - Iswar Hazarika
- Department of Pharmacology, Girijananda Chowdhury Institute of Pharmaceutical Science, Guwahati 781017, India
| | - Anju Das
- Department of Pharmacology, Royal School of Pharmacy, Royal Global University, Guwahati 781035, India
| | - Subash C. B. Gopinath
- Faculty of Chemical Engineering Technology, Universiti Malaysia Perlis (UniMAP), Arau, 02600 Perlis, Malaysia
- Institute of Nano Electronic Engineering, Universiti Malaysia Perlis, Kangar, 01000 Perlis, Malaysia
| | - Mariappan Rajan
- Department of Natural Products Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, India
| | - Mahendran Sekar
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Health Sciences, Royal College of Medicine Perak, Universiti Kuala Lumpur, Ipoh 30450, Perak, Malaysia
| | - Vetriselvan Subramaniyan
- Department of Pharmacology, School of Medicine, Faculty of Medicine, Bioscience and Nursing, MAHSA University, Selangor 42610, Malaysia
| | | | - Shivkanya Fuloria
- Faculty of Pharmacy, AIMST University, Semeling, Bedong, Kedah 08100, Malaysia
| | - Kalaivani Batumalaie
- Department of Biomedical Sciences, Faculty of Health Sciences, Asia Metropolitan University, 81750 Johor Bahru, Malaysia
| | - Yuan Seng Wu
- Centre for Virus and Vaccine Research, School of Medical and Life Sciences, Sunway University, Selangor 47500, Malaysia
- Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Selangor 47500, Malaysia
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In Vitro Angiogenesis Inhibition and Endothelial Cell Growth and Morphology. Int J Mol Sci 2022; 23:ijms23084277. [PMID: 35457095 PMCID: PMC9025250 DOI: 10.3390/ijms23084277] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 04/04/2022] [Accepted: 04/08/2022] [Indexed: 02/05/2023] Open
Abstract
A co-culture assay with human umbilical vein endothelial cells (HUVECs) and normal human dermal fibroblasts (NHDFs) was used to study whether selected angiogenesis inhibitors were able to inhibit differentiation and network formation of HUVECs in vitro. The effect of the inhibitors was determined by the morphology and the calculated percentage area covered by HUVECs. Neutralizing VEGF with avastin and polyclonal goat anti-VEGF antibody and inhibiting VEGFR2 with sorafenib and vatalanib resulted in the formation of HUVEC clusters of variable sizes as a result of inhibited EC differentiation. Furthermore, numerous inhibitors of the VEGF signaling pathways were tested for their effect on the growth and differentiation of HUVECs. The effects of these inhibitors did not reveal a cluster morphology, either individually or when combined to block VEGFR2 downstream pathways. Only the addition of N-methyl-p-bromolevamisole revealed a similar morphology as when targeting VEGF and VEGFR2, meaning it may have an inhibitory influence directly on VEGFR signaling. Additionally, several nuclear receptor ligands and miscellaneous compounds that might affect EC growth and differentiation were tested, but only dexamethasone gave rise to cluster formation similarly to VEGF-neutralizing compounds. These results point to a link between angiogenesis, HUVEC differentiation and glucocorticoid receptor activation.
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Wang D, Fu Z, Gao L, Zeng J, Xiang Y, Zhou L, Tong X, Wang XQ, Lu J. Increased IRF9-STAT2 signaling leads to adaptive resistance toward targeted therapy in melanoma by restraining GSDME-dependent pyroptosis. J Invest Dermatol 2022; 142:2476-2487.e9. [PMID: 35148998 DOI: 10.1016/j.jid.2022.01.024] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 01/12/2022] [Accepted: 01/18/2022] [Indexed: 12/28/2022]
Abstract
Melanoma is the leading cause of cutaneous malignancy death. BRAF inhibitors (BRAFis) have been developed as target therapies because nearly half of melanoma patients have activating mutations in the BRAF oncogene. However, the fast-developed resistance of BRAFis limits its treatment efficacy. Understanding the molecular mechanism of resistance is vital to increase the success of clinical treatment. We searched three datasets (GSE42872, GSE52882, and GSE106321) from the Gene Expression Omnibus (GEO), which analyzed the mRNA expression profile in melanoma cells under BRAFis treatment, and the differentially expressed genes (DEGs) were identified. Among all the DEGs, increased expression of IRF9 and STAT2 was distinguished and verified to be upregulated in BRAFis-treated melanoma cells. Furthermore, IRF9 or STAT2 overexpression led to less sensitivity, while IRF9 or STAT2 knockdown increased sensitivity to BRAFis treatment. In a subcutaneous xenograft tumor model, we demonstrated that IRF9 or STAT2 overexpression slowed BRAFis-induced tumor shrank, but IRF9 or STAT2 knockdown led to BRAFis-induced tumor shrank more quickly. More interestingly, we discovered that IRF9-STAT2 signaling controlled GSDME-dependent pyroptosis by restoring GSDME transcription. These results suggest that targeting IRF9/STAT2 may lead to more promising effective treatments to prevent melanoma resistance to BRAFis by inducing pyroptosis.
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Affiliation(s)
- Dan Wang
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, 410013 P. R. China
| | - Zhibing Fu
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, 410013 P. R. China
| | - Lihua Gao
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, 410013 P. R. China
| | - Jinrong Zeng
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, 410013 P. R. China
| | - Yaping Xiang
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, 410013 P. R. China
| | - Lu Zhou
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, 410013 P. R. China
| | - Xiaoliang Tong
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, 410013 P. R. China
| | - Xiao-Qi Wang
- Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Jianyun Lu
- Department of Dermatology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, 410013 P. R. China.
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26
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Pedersen S, Larsen KO, Christensen AH, Svane IM, Zerahn B, Ellebaek E. Cardiotoxicity in metastatic melanoma patients treated with BRAF and MEK inhibitors in a real-world setting. Acta Oncol 2022; 61:45-51. [PMID: 34666597 DOI: 10.1080/0284186x.2021.1992010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Combination therapy with BRAF and MEK inhibitors (BRAF/MEKi) has significantly improved the outcome for patients with BRAF-mutated melanoma. A reduction in left ventricular ejection fraction (LVEF) is a known side effect during treatment with BRAF/MEKi. This study aimed to analyze sequential multigated acquisition (MUGA) scans for the evaluation of LVEF and provide real-world data on cardiotoxicity induced by BRAF/MEKi in advanced melanoma. METHODS All patients with advanced melanoma treated with dabrafenib and trametinib at Herlev and Gentofte Hospital, Denmark, between March 2015 and September 2019, were included retrospectively. MUGA scans performed at baseline and every three months during treatment were analyzed. Cardiotoxicity was defined as a decline of ≥10 percentage point (pp) to an LVEF <50% (major cardiotoxicity) or a decline in LVEF of ≥15 pp but remaining >50% (minor cardiotoxicity). RESULTS A total of 139 patients were included. Forty-six patients (33%) met our criteria for cardiotoxicity; 31 patients (22%) experienced minor cardiotoxicity and 15 patients (11%) experienced major cardiotoxicity. Median time to decline in LVEF was 94 days, and all clinically significant declines in LVEF occurred before evaluation at six months. Reversibility of LVEF was seen in 80% of patients, three patients were not evaluable for reversibility. A low left ventricular peak emptying rate adjusted for heart rate (LVPERadj) at baseline was found a potential risk factor for the development of major cardiotoxicity (RR = 0.159, p = 0.001). CONCLUSION A decline in LVEF is common for patients with advanced melanoma treated with BRAF/MEKi but rarely clinically significant. No significant decline in LVEF was observed after evaluation at six months, therefore routine monitoring of LVEF might be stopped after six to nine months of BRAF/MEKi therapy. A low LVPERadj might be a risk factor for the development of cardiotoxicity and is suggested for further investigation.
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Affiliation(s)
- Sidsel Pedersen
- Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, Herlev, Denmark
| | - Kirstine Ostenfeld Larsen
- Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, Herlev, Denmark
| | - Alex Hørby Christensen
- Department of Cardiology, Copenhagen University Hospital, Herlev and Gentofte, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Inge Marie Svane
- Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, Herlev, Denmark
| | - Bo Zerahn
- Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital, Herlev and Gentofte, Herlev, Denmark
| | - Eva Ellebaek
- Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte, Herlev, Denmark
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Huang S, Deng W, Wang P, Yan Y, Xie C, Cao X, Chen M, Zhang C, Shi D, Dong Y, Cheng P, Xu H, Zhu W, Hu Z, Tang B, Zhu J. Fermitin family member 2 promotes melanoma progression by enhancing the binding of p-α-Pix to Rac1 to activate the MAPK pathway. Oncogene 2021; 40:5626-5638. [PMID: 34321603 PMCID: PMC8445820 DOI: 10.1038/s41388-021-01954-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 06/06/2021] [Accepted: 07/09/2021] [Indexed: 01/02/2023]
Abstract
We identified fermitin family member 2 (FERMT2, also known as kindlin-2) as a potential target in A375 cell line by siRNA library screening. Drugs that target mutant BRAF kinase lack durable efficacy in the treatment of melanoma because of acquired resistance, thus the identification of novel therapeutic targets is needed. Immunohistochemistry was used to identify kindlin-2 expression in melanoma samples. The interaction between kindlin-2 and Rac1 or p-Rac/Cdc42 guanine nucleotide exchange factor 6 (α-Pix) was investigated. Finally, the tumor suppressive role of kindlin-2 was validated in vitro and in vivo. Analysis of clinical samples and Oncomine data showed that higher levels of kindlin-2 predicted a more advanced T stage and M stage and facilitated metastasis and recurrence. Kindlin-2 knockdown significantly inhibited melanoma growth and migration, whereas kindlin-2 overexpression had the inverse effects. Further study showed that kindlin-2 could specifically bind to p-α-Pix(S13) and Rac1 to induce a switch from the inactive Rac1-GDP conformation to the active Rac1-GTP conformation and then stimulate the downstream MAPK pathway. Moreover, we revealed that a Rac1 inhibitor suppressed melanoma growth and metastasis and the combination of the Rac1 inhibitor and vemurafenib resulted in a better therapeutic outcome than monotherapy in melanoma with high kindlin-2 expression and BRAF mutation. Our results demonstrated that kindlin-2 promoted melanoma progression, which was attributed to specific binding to p-α-Pix(S13) and Rac1 to stimulate the downstream MAPK pathway. Thus, kindlin-2 could be a potential therapeutic target for treating melanoma.
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Affiliation(s)
- Shaobin Huang
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
- The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wuguo Deng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Peng Wang
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yue Yan
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Chuanbo Xie
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Xiaoling Cao
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Miao Chen
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Changlin Zhang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Dingbo Shi
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
| | - Yunxian Dong
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Pu Cheng
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hailin Xu
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wenkai Zhu
- Department of Chemistry, Portland State University, Portland, OR, USA
| | - Zhicheng Hu
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| | - Bing Tang
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
| | - Jiayuan Zhu
- The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
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Hey SP, Gerlach CV, Dunlap G, Prasad V, Kesselheim AS. The evidence landscape in precision medicine. Sci Transl Med 2021; 12:12/540/eaaw7745. [PMID: 32321867 DOI: 10.1126/scitranslmed.aaw7745] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 10/03/2019] [Indexed: 12/20/2022]
Abstract
Precision medicine is beginning to make an impact on the treatment of different diseases, but there are still challenges that must be overcome, such as the complexity of interventions, the need for marker validation, and the level of evidence necessary to demonstrate effectiveness. In this Perspective, we describe how evidence landscapes can help to address these challenges.
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Affiliation(s)
- Spencer Phillips Hey
- Harvard Center for Bioethics, Harvard Medical School, Boston, MA, USA. .,Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Cory V Gerlach
- Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA.,Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.,Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Garrett Dunlap
- Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA.,Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, and Therapeutics Graduate Program, Harvard Medical School, Boston, MA, USA
| | - Vinay Prasad
- Division of Hematology and Medical Oncology, Knight Cancer Institute, Department of Preventive Medicine and Public Health, and Center for Health Care Ethics, Oregon Health and Science University, Portland, OR, USA
| | - Aaron S Kesselheim
- Harvard Center for Bioethics, Harvard Medical School, Boston, MA, USA.,Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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Stagno A, Vari S, Annovazzi A, Anelli V, Russillo M, Cognetti F, Ferraresi V. Case Report: Rechallenge With BRAF and MEK Inhibitors in Metastatic Melanoma: A Further Therapeutic Option in Salvage Setting? Front Oncol 2021; 11:645008. [PMID: 34136385 PMCID: PMC8202400 DOI: 10.3389/fonc.2021.645008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 03/11/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND The combination of BRAF and MEK inhibitors represents the standard of care treatment for patients with metastatic BRAF-mutated melanoma, notwithstanding the high frequency of emergent resistance. Moreover, therapeutic options outside clinical trials are scarce when patients have progressed after both targeted therapy and therapy with immune checkpoint inhibitors. In this article, we report our experience with targeted therapy rechallenging with BRAF and MEK inhibitors in patients with metastatic BRAF-mutated melanoma after progression with kinase inhibitors and immunotherapy. METHODS Four patients with metastatic BRAF-mutated melanoma were rechallenged with BRAF and MEK inhibitors after progression with targeted therapy and subsequent immunotherapy (checkpoint inhibitors). RESULTS Two patients (one of them was heavily pretreated) had partial response over 36 months (with local treatment on oligoprogression disease) and 10 months, respectively. A third patient with multisite visceral disease and high serum levels of lactate dehydrogenase had a short-lived clinical benefit rapidly followed by massive progression of disease (early progressor). The fourth patient, currently on treatment with BRAF/MEK inhibitors, is showing a clinical benefit and radiological stable disease over 3 months of therapy. Adverse events were manageable, similar to those reported during the first targeted therapy; the treatment was better tolerated at rechallenge compared with the first treatment by two out of four patients.
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Affiliation(s)
- Anna Stagno
- Department of Medical Oncology 1, IRCCS-Regina Elena National Cancer Institute, Rome, Italy
| | - Sabrina Vari
- Department of Medical Oncology 1, IRCCS-Regina Elena National Cancer Institute, Rome, Italy
| | - Alessio Annovazzi
- Nuclear Medicine Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy
| | - Vincenzo Anelli
- Radiology and Diagnostic Imaging Unit, IRCCS-Regina Elena National Cancer Institute, Rome, Italy
| | - Michelangelo Russillo
- Department of Medical Oncology 1, IRCCS-Regina Elena National Cancer Institute, Rome, Italy
| | - Francesco Cognetti
- Department of Medical Oncology 1, IRCCS-Regina Elena National Cancer Institute, Rome, Italy
| | - Virginia Ferraresi
- Department of Medical Oncology 1, IRCCS-Regina Elena National Cancer Institute, Rome, Italy
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Wessely A, Steeb T, Berking C, Heppt MV. How Neural Crest Transcription Factors Contribute to Melanoma Heterogeneity, Cellular Plasticity, and Treatment Resistance. Int J Mol Sci 2021; 22:ijms22115761. [PMID: 34071193 PMCID: PMC8198848 DOI: 10.3390/ijms22115761] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 12/14/2022] Open
Abstract
Cutaneous melanoma represents one of the deadliest types of skin cancer. The prognosis strongly depends on the disease stage, thus early detection is crucial. New therapies, including BRAF and MEK inhibitors and immunotherapies, have significantly improved the survival of patients in the last decade. However, intrinsic and acquired resistance is still a challenge. In this review, we discuss two major aspects that contribute to the aggressiveness of melanoma, namely, the embryonic origin of melanocytes and melanoma cells and cellular plasticity. First, we summarize the physiological function of epidermal melanocytes and their development from precursor cells that originate from the neural crest (NC). Next, we discuss the concepts of intratumoral heterogeneity, cellular plasticity, and phenotype switching that enable melanoma to adapt to changes in the tumor microenvironment and promote disease progression and drug resistance. Finally, we further dissect the connection of these two aspects by focusing on the transcriptional regulators MSX1, MITF, SOX10, PAX3, and FOXD3. These factors play a key role in NC initiation, NC cell migration, and melanocyte formation, and we discuss how they contribute to cellular plasticity and drug resistance in melanoma.
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Affiliation(s)
- Anja Wessely
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (A.W.); (T.S.); (C.B.)
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
| | - Theresa Steeb
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (A.W.); (T.S.); (C.B.)
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
| | - Carola Berking
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (A.W.); (T.S.); (C.B.)
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
| | - Markus Vincent Heppt
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany; (A.W.); (T.S.); (C.B.)
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Correspondence: ; Tel.: +49-9131-85-35747
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McKenna S, García-Gutiérrez L. Resistance to Targeted Therapy and RASSF1A Loss in Melanoma: What Are We Missing? Int J Mol Sci 2021; 22:5115. [PMID: 34066022 PMCID: PMC8150731 DOI: 10.3390/ijms22105115] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 04/26/2021] [Accepted: 05/06/2021] [Indexed: 12/20/2022] Open
Abstract
Melanoma is one of the most aggressive forms of skin cancer and is therapeutically challenging, considering its high mutation rate. Following the development of therapies to target BRAF, the most frequently found mutation in melanoma, promising therapeutic responses were observed. While mono- and combination therapies to target the MAPK cascade did induce a therapeutic response in BRAF-mutated melanomas, the development of resistance to MAPK-targeted therapies remains a challenge for a high proportion of patients. Resistance mechanisms are varied and can be categorised as intrinsic, acquired, and adaptive. RASSF1A is a tumour suppressor that plays an integral role in the maintenance of cellular homeostasis as a central signalling hub. RASSF1A tumour suppressor activity is commonly lost in melanoma, mainly by aberrant promoter hypermethylation. RASSF1A loss could be associated with several mechanisms of resistance to MAPK inhibition considering that most of the signalling pathways that RASSF1A controls are found to be altered targeted therapy resistant melanomas. Herein, we discuss resistance mechanisms in detail and the potential role for RASSF1A reactivation to re-sensitise BRAF mutant melanomas to therapy.
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Affiliation(s)
| | - Lucía García-Gutiérrez
- Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland;
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Ahmed R, Muralidharan R, Srivastava A, Johnston SE, Zhao YD, Ekmekcioglu S, Munshi A, Ramesh R. Molecular Targeting of HuR Oncoprotein Suppresses MITF and Induces Apoptosis in Melanoma Cells. Cancers (Basel) 2021; 13:cancers13020166. [PMID: 33418925 PMCID: PMC7825065 DOI: 10.3390/cancers13020166] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 12/27/2020] [Accepted: 12/29/2020] [Indexed: 01/14/2023] Open
Abstract
Simple Summary The human antigen R (HuR) protein regulates the expression of hundreds of proteins in a cell that support tumor growth, drug resistance, and metastases. HuR is overexpressed in several human cancers, including melanoma, and is a molecular target for cancer therapy. Our study objective, therefore, was to develop HuR-targeted therapy for melanoma. We identified that HuR regulates the microphthalmia-associated transcription factor (MITF) that has been implicated in both intrinsic and acquired drug resistance in melanoma and is a putative therapeutic target in melanoma. Using a gene therapeutic approach, we demonstrated silencing of HuR reduced MITF protein expression and inhibited the growth of melanoma cells but not normal melanocytes. However, combining HuR-targeted therapy with a small molecule MEK inhibitor suppressed MITF and produced a synergistic antitumor activity against melanoma cells. Our study results demonstrate that HuR is a promising target for melanoma treatment and offers new combinatorial treatment strategies for overriding MITF-mediated drug resistance. Abstract Background: Treatment of metastatic melanoma possesses challenges due to drug resistance and metastases. Recent advances in targeted therapy and immunotherapy have shown clinical benefits in melanoma patients with increased survival. However, a subset of patients who initially respond to targeted therapy relapse and succumb to the disease. Therefore, efforts to identify new therapeutic targets are underway. Due to its role in stabilizing several oncoproteins’ mRNA, the human antigen R (HuR) has been shown as a promising molecular target for cancer therapy. However, little is known about its potential role in melanoma treatment. Methods: In this study, we tested the impact of siRNA-mediated gene silencing of HuR in human melanoma (MeWo, A375) and normal melanocyte cells in vitro. Cells were treated with HuR siRNA encapsulated in a lipid nanoparticle (NP) either alone or in combination with MEK inhibitor (U0126) and subjected to cell viability, cell-cycle, apoptosis, Western blotting, and cell migration and invasion assays. Cells that were untreated or treated with control siRNA-NP (C-NP) were included as controls. Results: HuR-NP treatment significantly reduced the expression of HuR and HuR-regulated oncoproteins, induced G1 cell cycle arrest, activated apoptosis signaling cascade, and mitigated melanoma cells’ aggressiveness while sparing normal melanocytes. Furthermore, we demonstrated that HuR-NP treatment significantly reduced the expression of the microphthalmia-associated transcription factor (MITF) in both MeWo and MITF-overexpressing MeWo cells (p < 0.05). Finally, combining HuR-NP with U0126 resulted in synergistic antitumor activity against MeWo cells (p < 0.01). Conclusion: HuR-NP exhibited antitumor activity in melanoma cells independent of their oncogenic B-RAF mutational status. Additionally, combinatorial therapy incorporating MEK inhibitor holds promise in overriding MITF-mediated drug resistance in melanoma.
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Affiliation(s)
- Rebaz Ahmed
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (R.A.); (R.M.); (A.S.)
- Graduate Program in Biomedical Sciences, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Ranganayaki Muralidharan
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (R.A.); (R.M.); (A.S.)
- Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (Y.D.Z.); (A.M.)
| | - Akhil Srivastava
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (R.A.); (R.M.); (A.S.)
- Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (Y.D.Z.); (A.M.)
| | - Sarah E. Johnston
- Department of Biostatistics and Epidemiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Yan D. Zhao
- Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (Y.D.Z.); (A.M.)
- Department of Biostatistics and Epidemiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Suhendan Ekmekcioglu
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Anupama Munshi
- Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (Y.D.Z.); (A.M.)
- Department of Radiation Oncology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Rajagopal Ramesh
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (R.A.); (R.M.); (A.S.)
- Graduate Program in Biomedical Sciences, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (Y.D.Z.); (A.M.)
- Correspondence: ; Tel.: +1-405-271-6101
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Kumar PR, Moore JA, Bowles KM, Rushworth SA, Moncrieff MD. Mitochondrial oxidative phosphorylation in cutaneous melanoma. Br J Cancer 2021; 124:115-123. [PMID: 33204029 PMCID: PMC7782830 DOI: 10.1038/s41416-020-01159-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 10/28/2020] [Accepted: 10/29/2020] [Indexed: 12/14/2022] Open
Abstract
The Warburg effect in tumour cells is associated with the upregulation of glycolysis to generate ATP, even under normoxic conditions and the presence of fully functioning mitochondria. However, scientific advances made over the past 15 years have reformed this perspective, demonstrating the importance of oxidative phosphorylation (OXPHOS) as well as glycolysis in malignant cells. The metabolic phenotypes in melanoma display heterogeneic dynamism (metabolic plasticity) between glycolysis and OXPHOS, conferring a survival advantage to adapt to harsh conditions and pathways of chemoresistance. Furthermore, the simultaneous upregulation of both OXPHOS and glycolysis (metabolic symbiosis) has been shown to be vital for melanoma progression. The tumour microenvironment (TME) has an essential supporting role in promoting progression, invasion and metastasis of melanoma. Mesenchymal stromal cells (MSCs) in the TME show a symbiotic relationship with melanoma, protecting tumour cells from apoptosis and conferring chemoresistance. With the significant role of OXPHOS in metabolic plasticity and symbiosis, our review outlines how mitochondrial transfer from MSCs to melanoma tumour cells plays a key role in melanoma progression and is the mechanism by which melanoma cells regain OXPHOS capacity even in the presence of mitochondrial mutations. The studies outlined in this review indicate that targeting mitochondrial trafficking is a potential novel therapeutic approach for this highly refractory disease.
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Affiliation(s)
- Prakrit R Kumar
- Bob Champion Research and Education Building, Norwich Medical School, University of East Anglia, Norwich, UK
| | - Jamie A Moore
- Bob Champion Research and Education Building, Norwich Medical School, University of East Anglia, Norwich, UK
| | - Kristian M Bowles
- Bob Champion Research and Education Building, Norwich Medical School, University of East Anglia, Norwich, UK
- Department of Haematology, Norfolk and Norwich University Hospital, Norwich, UK
| | - Stuart A Rushworth
- Bob Champion Research and Education Building, Norwich Medical School, University of East Anglia, Norwich, UK.
| | - Marc D Moncrieff
- Bob Champion Research and Education Building, Norwich Medical School, University of East Anglia, Norwich, UK.
- Department of Plastic and Reconstructive Surgery, Norfolk and Norwich University Hospital, Norwich, NR4 7UY, UK.
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HER3-Receptor-Mediated STAT3 Activation Plays a Central Role in Adaptive Resistance toward Vemurafenib in Melanoma. Cancers (Basel) 2020; 12:cancers12123761. [PMID: 33327495 PMCID: PMC7764938 DOI: 10.3390/cancers12123761] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 12/02/2020] [Accepted: 12/09/2020] [Indexed: 01/18/2023] Open
Abstract
Simple Summary The major obstacle for the long-term success of targeted therapies in melanoma is the occurrence of resistance. Here, we present a new mechanism of targeted therapy resistance in melanoma where the treatment with the BRAF inhibitor vemurafenib causes an increased activation of HER3 via shed ligands. This is followed by an activation of STAT3 via HER3 and results in the expression of the STAT3 target gene SOX2. Pharmacological inhibition of HERs sensitizes melanoma cells toward vemurafenib treatment. Thus, blocking HER family members and especially HER3 in addition to targeted therapy treatment might prevent the occurrence of resistance. Abstract Melanoma is an aggressive form of skin cancer that is often characterized by activating mutations in the Mitogen-Activated Protein (MAP) kinase pathway, causing hyperproliferation of the cancer cells. Thus, inhibitors targeting this pathway were developed. These inhibitors are initially very effective, but the occurrence of resistance eventually leads to a failure of the therapy and is the major obstacle for clinical success. Therefore, investigating the mechanisms causing resistance and discovering ways to overcome them is essential for the success of therapy. Here, we observed that treatment of melanoma cells with the B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) inhibitor vemurafenib caused an increased cell surface expression and activation of human epidermal growth factor receptor 3 (HER3) by shed ligands. HER3 promoted the activation of signal transducer and activator of transcription 3 (STAT3) resulting in upregulation of the STAT3 target gene SRY-Box Transcription Factor 2 (SOX2) and survival of the cancer cells. Pharmacological blocking of HER led to a diminished STAT3 activation and increased sensitivity toward vemurafenib. Moreover, HER blocking sensitized vemurafenib-resistant cells to drug treatment. We conclude that the inhibition of the STAT3 upstream regulator HER might help to overcome melanoma therapy resistance toward targeted therapies.
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Vanni I, Casula M, Pastorino L, Manca A, Dalmasso B, Andreotti V, Pisano M, Colombino M, Pfeffer U, Tanda ET, Rozzo C, Paliogiannis P, Cossu A, Ghiorzo P, Palmieri G. Quality assessment of a clinical next-generation sequencing melanoma panel within the Italian Melanoma Intergroup (IMI). Diagn Pathol 2020; 15:143. [PMID: 33317587 PMCID: PMC7737361 DOI: 10.1186/s13000-020-01052-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 11/04/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Identification of somatic mutations in key oncogenes in melanoma is important to lead the effective and efficient use of personalized anticancer treatment. Conventional methods focus on few genes per run and, therefore, are unable to screen for multiple genes simultaneously. The use of Next-Generation Sequencing (NGS) technologies enables sequencing of multiple cancer-driving genes in a single assay, with reduced costs and DNA quantity needed and increased mutation detection sensitivity. METHODS We designed a customized IMI somatic gene panel for targeted sequencing of actionable melanoma mutations; this panel was tested on three different NGS platforms using 11 metastatic melanoma tissue samples in blinded manner between two EMQN quality certificated laboratory. RESULTS The detection limit of our assay was set-up to a Variant Allele Frequency (VAF) of 10% with a coverage of at least 200x. All somatic variants detected by all NGS platforms with a VAF ≥ 10%, were also validated by an independent method. The IMI panel achieved a very good concordance among the three NGS platforms. CONCLUSION This study demonstrated that, using the main sequencing platforms currently available in the diagnostic setting, the IMI panel can be adopted among different centers providing comparable results.
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Affiliation(s)
- Irene Vanni
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, L.go R Benzi, 10, 16132, Genoa, Italy
- Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
| | - Milena Casula
- Unit of Cancer Genetics, National Research Council (CNR), Sassari, Italy
| | - Lorenza Pastorino
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, L.go R Benzi, 10, 16132, Genoa, Italy
- Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
| | - Antonella Manca
- Unit of Cancer Genetics, National Research Council (CNR), Sassari, Italy
| | - Bruna Dalmasso
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, L.go R Benzi, 10, 16132, Genoa, Italy
- Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
| | - Virginia Andreotti
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, L.go R Benzi, 10, 16132, Genoa, Italy
- Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
| | - Marina Pisano
- Unit of Cancer Genetics, National Research Council (CNR), Sassari, Italy
| | - Maria Colombino
- Unit of Cancer Genetics, National Research Council (CNR), Sassari, Italy
| | - Ulrich Pfeffer
- Tumor Epigenetics, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | | | - Carla Rozzo
- Unit of Cancer Genetics, National Research Council (CNR), Sassari, Italy
| | - Panagiotis Paliogiannis
- Department of Medical, Surgical, and Experimental Sciences, University of Sassari, Sassari, Italy
| | - Antonio Cossu
- Unit of Cancer Genetics, National Research Council (CNR), Sassari, Italy
| | - Paola Ghiorzo
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, L.go R Benzi, 10, 16132, Genoa, Italy.
- Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy.
| | - Giuseppe Palmieri
- Unit of Cancer Genetics, National Research Council (CNR), Sassari, Italy
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Vanni I, Tanda ET, Dalmasso B, Pastorino L, Andreotti V, Bruno W, Boutros A, Spagnolo F, Ghiorzo P. Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications. Front Mol Biosci 2020; 7:172. [PMID: 32850962 PMCID: PMC7396525 DOI: 10.3389/fmolb.2020.00172] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 07/03/2020] [Indexed: 02/06/2023] Open
Abstract
Melanoma is one of the most aggressive tumors of the skin, and its incidence is growing worldwide. Historically considered a drug resistant disease, since 2011 the therapeutic landscape of melanoma has radically changed. Indeed, the improved knowledge of the immune system and its interactions with the tumor, and the ever more thorough molecular characterization of the disease, has allowed the development of immunotherapy on the one hand, and molecular target therapies on the other. The increased availability of more performing technologies like Next-Generation Sequencing (NGS), and the availability of increasingly large genetic panels, allows the identification of several potential therapeutic targets. In light of this, numerous clinical and preclinical trials are ongoing, to identify new molecular targets. Here, we review the landscape of mutated non-BRAF skin melanoma, in light of recent data deriving from Whole-Exome Sequencing (WES) or Whole-Genome Sequencing (WGS) studies on melanoma cohorts for which information on the mutation rate of each gene was available, for a total of 10 NGS studies and 992 samples, focusing on available, or in experimentation, targeted therapies beyond those targeting mutated BRAF. Namely, we describe 33 established and candidate driver genes altered with frequency greater than 1.5%, and the current status of targeted therapy for each gene. Only 1.1% of the samples showed no coding mutations, whereas 30% showed at least one mutation in the RAS genes (mostly NRAS) and 70% showed mutations outside of the RAS genes, suggesting potential new roads for targeted therapy. Ongoing clinical trials are available for 33.3% of the most frequently altered genes.
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Affiliation(s)
- Irene Vanni
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genova, Italy
| | | | - Bruna Dalmasso
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genova, Italy
| | - Lorenza Pastorino
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genova, Italy
| | - Virginia Andreotti
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genova, Italy
| | - William Bruno
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genova, Italy
| | - Andrea Boutros
- Medical Oncology, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | | | - Paola Ghiorzo
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genova, Italy
- Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genova, Italy
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Tanda ET, Vanni I, Boutros A, Andreotti V, Bruno W, Ghiorzo P, Spagnolo F. Current State of Target Treatment in BRAF Mutated Melanoma. Front Mol Biosci 2020; 7:154. [PMID: 32760738 PMCID: PMC7371970 DOI: 10.3389/fmolb.2020.00154] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Accepted: 06/19/2020] [Indexed: 12/17/2022] Open
Abstract
Incidence of melanoma has been constantly growing during the last decades. Although most of the new diagnoses are represented by thin melanomas, the number of melanoma-related deaths in 2018 was 60,712 worldwide (Global Cancer Observatory, 2019). Until 2011, no systemic therapy showed to improve survival in patients with advanced or metastatic melanoma. At that time, standard of care was chemotherapy, with very limited results. The identification of BRAF V600 mutation, and the subsequent introduction of BRAF targeting drugs, radically changed the clinical practice and dramatically improved outcomes. In this review, we will retrace the development of molecular-target drugs and the current therapeutic scenario for patients with BRAF mutated melanoma, from the introduction of BRAF inhibitors as single agents to modern clinical practice. We will also discuss the resistance mechanisms identified so far, and the future therapeutic perspectives in BRAF mutated melanoma.
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Affiliation(s)
| | - Irene Vanni
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
| | - Andrea Boutros
- Medical Oncology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Virginia Andreotti
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
| | - William Bruno
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
| | - Paola Ghiorzo
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
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Ferraz CAA, de Oliveira Júnior RG, de Oliveira AP, Groult H, Beaugeard L, Picot L, de Alencar Filho EB, Almeida JRGDS, Nunes XP. Complexation with β-cyclodextrin enhances apoptosis-mediated cytotoxic effect of harman in chemoresistant BRAF-mutated melanoma cells. Eur J Pharm Sci 2020; 150:105353. [PMID: 32334103 DOI: 10.1016/j.ejps.2020.105353] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/27/2020] [Accepted: 04/15/2020] [Indexed: 10/24/2022]
Abstract
Harman, a natural β-carboline alkaloid, has recently gained considerable interest due to its anticancer properties. However, its physicochemical characteristics and poor oral bioavailability have been limiting factors for its pharmaceutical development. In this paper, we described the complexation of harman (HAR) with β-cyclodextrin (βCD) as a promising alternative to improve its solubility and consequently its cytotoxic effect in chemoresistant melanoma cells (A2058 cell line). Inclusion complexes (βCD-HAR) were prepared using a simple method and then characterized by FTIR, NMR and SEM techniques. Through in silico studies, the mechanism of complexation of HAR with βCD was elucidated in detail. Both HAR and βCD-HAR promoted cytotoxicity, apoptosis, cell cycle arrest and inhibition of cell migration in melanoma cells. Interestingly, complexation of HAR with βCD enhanced its pro-apoptotic effect by increasing of caspase-3 activity (p < 0.05), probably due to an improvement in HAR solubility. In addition, HAR and βCD-HAR sensitized A2058 cells to vemurafenib, dacarbazine and 5FU treatments, potentializing their cytotoxic activity. These findings suggest that complexation of HAR with natural polymers such as βCD can be useful to improve its bioavailability and antimelanoma activity.
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Affiliation(s)
- Christiane Adrielly Alves Ferraz
- NEPLAME, Universidade Federal do Vale do São Francisco, Petrolina-PE, 56306-000, Brazil; RENORBIO, Universidade Federal Rural de Pernambuco, Recife-PE, 52171-900, Brazil
| | | | - Ana Paula de Oliveira
- NEPLAME, Universidade Federal do Vale do São Francisco, Petrolina-PE, 56306-000, Brazil
| | - Hugo Groult
- UMRi CNRS 7266 LIENSs, La Rochelle Université, La Rochelle, 17042, France
| | - Laureen Beaugeard
- UMRi CNRS 7266 LIENSs, La Rochelle Université, La Rochelle, 17042, France
| | - Laurent Picot
- UMRi CNRS 7266 LIENSs, La Rochelle Université, La Rochelle, 17042, France
| | | | | | - Xirley Pereira Nunes
- NEPLAME, Universidade Federal do Vale do São Francisco, Petrolina-PE, 56306-000, Brazil.
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Vanni I, Tanda ET, Spagnolo F, Andreotti V, Bruno W, Ghiorzo P. The Current State of Molecular Testing in the BRAF-Mutated Melanoma Landscape. Front Mol Biosci 2020; 7:113. [PMID: 32695793 PMCID: PMC7338720 DOI: 10.3389/fmolb.2020.00113] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 05/13/2020] [Indexed: 01/19/2023] Open
Abstract
The incidence of melanoma, among the most lethal cancers, is widespread and increasing. Metastatic melanoma has a poor prognosis, representing about 90% of skin cancer mortality. The increased knowledge of tumor biology and the greater understanding of the immune system role in the anti-tumor response has allowed us to develop a more rational approach to systemic therapies. The discovery of activating BRAF mutations in half of all melanomas has led to the development of molecularly targeted therapy with BRAF and MEK inhibitors, which dramatically improved outcomes of patients with stage IV BRAF-mutant melanoma. More recently, the results of clinical phase III studies conducted in the adjuvant setting led to the combined administration of BRAF and MEK inhibitors also in patients with resected high-risk melanoma (stage III). Therefore, BRAF mutation testing has become a priority to determine the oncologist's choice and course of therapy. In this review, we will report the molecular biology-based strategies used for BRAF mutation detection with the main advantages and disadvantages of the most commonly used diagnostic strategies. The timing of such molecular assessment in patients with cutaneous melanoma will be discussed, and we will also examine considerations and approaches for accurate and effective BRAF testing.
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Affiliation(s)
- Irene Vanni
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
| | | | | | - Virginia Andreotti
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
| | - William Bruno
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
| | - Paola Ghiorzo
- Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Genetics of Rare Cancers, Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
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Czarnecka AM, Bartnik E, Fiedorowicz M, Rutkowski P. Targeted Therapy in Melanoma and Mechanisms of Resistance. Int J Mol Sci 2020; 21:ijms21134576. [PMID: 32605090 PMCID: PMC7369697 DOI: 10.3390/ijms21134576] [Citation(s) in RCA: 127] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/18/2020] [Accepted: 06/19/2020] [Indexed: 12/11/2022] Open
Abstract
The common mutation BRAFV600 in primary melanomas activates the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway and the introduction of proto-oncogene B-Raf (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors (BRAFi and MEKi) was a breakthrough in the treatment of these cancers. However, 15–20% of tumors harbor primary resistance to this therapy, and moreover, patients develop acquired resistance to treatment. Understanding the molecular phenomena behind resistance to BRAFi/MEKis is indispensable in order to develop novel targeted therapies. Most often, resistance develops due to either the reactivation of the MAPK/ERK pathway or the activation of alternative kinase signaling pathways including phosphatase and tensin homolog (PTEN), neurofibromin 1 (NF-1) or RAS signaling. The hyperactivation of tyrosine kinase receptors, such as the receptor of the platelet-derived growth factor β (PDFRβ), insulin-like growth factor 1 receptor (IGF-1R) and the receptor for hepatocyte growth factor (HGF), lead to the induction of the AKT/3-phosphoinositol kinase (PI3K) pathway. Another pathway resulting in BRAFi/MEKi resistance is the hyperactivation of epidermal growth factor receptor (EGFR) signaling or the deregulation of microphthalmia-associated transcription factor (MITF).
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Affiliation(s)
- Anna M. Czarnecka
- Department of Soft Tissue/Bone, Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland;
- Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland
- Correspondence:
| | - Ewa Bartnik
- Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 02-106 Warsaw, Poland;
- Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland
| | - Michał Fiedorowicz
- Small Animal Magnetic Resonance Imaging Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland;
- Interinstitute Laboratory of New Diagnostic Applications of MRI, Nalecz Institute of Biocybernetics and Biomedical Engineering, Polish Academy of Sciences, 02-109 Warsaw, Poland
| | - Piotr Rutkowski
- Department of Soft Tissue/Bone, Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland;
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Polymethoxyflavones from Gardenia oudiepe (Rubiaceae) induce cytoskeleton disruption-mediated apoptosis and sensitize BRAF-mutated melanoma cells to chemotherapy. Chem Biol Interact 2020; 325:109109. [PMID: 32376239 DOI: 10.1016/j.cbi.2020.109109] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 03/18/2020] [Accepted: 04/13/2020] [Indexed: 11/21/2022]
Abstract
A series of 10 natural and semisynthetic flavonoids (1 to 10) were obtained from Gardenia oudiepe (Rubiaceae), an endemic plant from New Caledonia. Most of them were polymethoxylated flavones (PMFs) of rare occurrence. After a cell viability screening test, PMFs 2 and 3 showed significant cytotoxic activity against A2058 human melanoma cells (IC50 = 3.92 and 8.18 μM, respectively) and were selected for in-depth pharmacological assays. Both compounds inhibited cell migration and induced apoptosis and cell cycle arrest after 72h of treatment. Immunofluorescence assays indicated that these outcomes were possibly related to the induction of cytoskeleton disruption associated to actin and tubulin depolymerization. These data were confirmed by molecular docking studies, which showed a good interaction between PMFs 2 and 3 and tubulin, particularly at the colchicine binding site. As A2058 are considered as chemoresistant to conventional chemotherapy, compounds 2 and 3 (½IC50) were associated to clinically-used antimelanoma drugs (vemurafenib and dacarbazine) and combined therapies efficacy was assessed by the MTT assay. PMFs 2 restored the sensitivity of A2058 cells to dacarbazine treatment (IC50 = 49.38 μM vs. >100 μM). Taken together, these data suggest that PMFs from G. oudiepe could be potential leaders for the design of new antimelanoma drugs.
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Alqathama A. BRAF in malignant melanoma progression and metastasis: potentials and challenges. Am J Cancer Res 2020; 10:1103-1114. [PMID: 32368388 PMCID: PMC7191094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 03/05/2020] [Indexed: 06/11/2023] Open
Abstract
Recent advances in gene sequencing have shown that activated BRAF mutations are present in more than 50% of malignant melanomas and contribute to constitutive signals in the MAPK pathway. Besides the importance of its mutations in cell proliferation, BRAF is associated with lymph node, brain and liver metastasis, along with the loss of PTEN expression and ATG5. Knowledge of this genetic alteration has led to the development of personalized and targeted therapy strategies which block different pathways driving melanoma pathogenesis. Several targeted therapy agents such as vemurafenib, dabrafenib and encorafenib have been approved by the FDA as BRAF inhibitors, as well as other immunotherapies such as anti-CTLA-4 (ipilimumab). However, one of the main challenges is acquired resistance via reactivation of MAPK via CRAF/COT overexpression. Resistance to current BRAF inhibitors is a clinical challenge and one of the strategies to overcome this phenomenon is combination treatment, with the most recently approved combination being BRAF/MEK inhibitors (dabrafenib and trametinib) and BRAF or MEK inhibitors with immunocheckpoint blockers. This review delineates the current role of BRAF in melanoma progression and metastasis. It discusses targeted therapies and resistance mechanisms to BRAF inhibitors, and illustrates strategies to overcome this mechanism with recently approved agents.
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Affiliation(s)
- Aljawharah Alqathama
- Department of Pharmacognosy, Faculty of Pharmacy, Umm Al-Qura University Makkah, Saudi Arabia
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de Oliveira-Júnior RG, Nicolau E, Bonnet A, Prunier G, Beaugeard L, Joguet N, Thiéry V, Picot L. Carotenoids from Rhodomonas salina Induce Apoptosis and Sensitize A2058 Melanoma Cells to Chemotherapy. REVISTA BRASILEIRA DE FARMACOGNOSIA 2020. [DOI: 10.1007/s43450-020-00036-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Current Advances in the Treatment of BRAF-Mutant Melanoma. Cancers (Basel) 2020; 12:cancers12020482. [PMID: 32092958 PMCID: PMC7072236 DOI: 10.3390/cancers12020482] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 02/02/2020] [Accepted: 02/14/2020] [Indexed: 12/12/2022] Open
Abstract
Melanoma is the most lethal form of skin cancer. Melanoma is usually curable with surgery if detected early, however, treatment options for patients with metastatic melanoma are limited and the five-year survival rate for metastatic melanoma had been 15-20% before the advent of immunotherapy. Treatment with immune checkpoint inhibitors has increased long-term survival outcomes in patients with advanced melanoma to as high as 50% although individual response can vary greatly. A mutation within the MAPK pathway leads to uncontrollable growth and ultimately develops into cancer. The most common driver mutation that leads to this characteristic overactivation in the MAPK pathway is the B-RAF mutation. Current combinations of BRAF and MEK inhibitors that have demonstrated improved patient outcomes include dabrafenib with trametinib, vemurafenib with cobimetinib or encorafenib with binimetinib. Treatment with BRAF and MEK inhibitors has met challenges as patient responses began to drop due to the development of resistance to these inhibitors which paved the way for development of immunotherapies and other small molecule inhibitor approaches to address this. Resistance to these inhibitors continues to push the need to expand our understanding of novel mechanisms of resistance associated with treatment therapies. This review focuses on the current landscape of how resistance occurs with the chronic use of BRAF and MEK inhibitors in BRAF-mutant melanoma and progress made in the fields of immunotherapies and other small molecules when used alone or in combination with BRAF and MEK inhibitors to delay or circumvent the onset of resistance for patients with stage III/IV BRAF mutant melanoma.
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Monti M, Consoli F, Vescovi R, Bugatti M, Vermi W. Human Plasmacytoid Dendritic Cells and Cutaneous Melanoma. Cells 2020; 9:E417. [PMID: 32054102 PMCID: PMC7072514 DOI: 10.3390/cells9020417] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 02/05/2020] [Accepted: 02/07/2020] [Indexed: 12/12/2022] Open
Abstract
The prognosis of metastatic melanoma (MM) patients has remained poor for a long time. However, the recent introduction of effective target therapies (BRAF and MEK inhibitors for BRAFV600-mutated MM) and immunotherapies (anti-CTLA-4 and anti-PD-1) has significantly improved the survival of MM patients. Notably, all these responses are highly dependent on the fitness of the host immune system, including the innate compartment. Among immune cells involved in cancer immunity, properly activated plasmacytoid dendritic cells (pDCs) exert an important role, bridging the innate and adaptive immune responses and directly eliminating cancer cells. A distinctive feature of pDCs is the production of high amount of type I Interferon (I-IFN), through the Toll-like receptor (TLR) 7 and 9 signaling pathway activation. However, published data indicate that melanoma-associated escape mechanisms are in place to hijack pDC functions. We have recently reported that pDC recruitment is recurrent in the early phases of melanoma, but the entire pDC compartment collapses over melanoma progression. Here, we summarize recent advances on pDC biology and function within the context of melanoma immunity.
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Affiliation(s)
- Matilde Monti
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (M.M.); (R.V.); (M.B.)
| | - Francesca Consoli
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology, University of Brescia at ASST-Spedali Civili, 25123 Brescia, Italy;
| | - Raffaella Vescovi
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (M.M.); (R.V.); (M.B.)
| | - Mattia Bugatti
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (M.M.); (R.V.); (M.B.)
| | - William Vermi
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (M.M.); (R.V.); (M.B.)
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
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Li QS, Shen BN, Xu HJ, Ruan BF. Promising Strategies for Overcoming BRAF Inhibitor Resistance Based on Known Resistance Mechanisms. Anticancer Agents Med Chem 2020; 20:1415-1430. [PMID: 32321411 DOI: 10.2174/1871520620666200422073622] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 01/23/2020] [Accepted: 02/06/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Almost 50% of metastatic melanomas harbor BRAF mutations. Since 2011, BRAF inhibitors have exhibited striking clinical benefits in BRAF-mutant melanoma patients. Unfortunately, their therapeutic effects are often temporary. The resistance mechanisms vary and can be broadly classified as MAPK reactivation-dependent and -independent. Elucidation of these resistance mechanisms provides new insights into strategies for overcoming resistance. Indeed, several alternative treatment strategies, including changes in the mode of administration, combinations of BRAF and MEK inhibitors, and immunotherapy have been verified as beneficial to BRAF inhibitor-resistant melanoma patients. Prospect In this review, we discuss promising strategies for overcoming drug resistance and highlighting the prospects for discovering strategies to counteract BRAF inhibitor resistance.
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Affiliation(s)
- Qing-Shan Li
- School of Food and Biological Engineering, Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei University of Technology, Hefei, 230601, China
| | - Bang-Nian Shen
- School of Food and Biological Engineering, Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei University of Technology, Hefei, 230601, China
| | - Hua-Jian Xu
- School of Food and Biological Engineering, Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei University of Technology, Hefei, 230601, China
| | - Ban-Feng Ruan
- School of Food and Biological Engineering, Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei University of Technology, Hefei, 230601, China
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Huertas CS, Calvo-Lozano O, Mitchell A, Lechuga LM. Advanced Evanescent-Wave Optical Biosensors for the Detection of Nucleic Acids: An Analytic Perspective. Front Chem 2019; 7:724. [PMID: 31709240 PMCID: PMC6823211 DOI: 10.3389/fchem.2019.00724] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 10/10/2019] [Indexed: 12/19/2022] Open
Abstract
Evanescent-wave optical biosensors have become an attractive alternative for the screening of nucleic acids in the clinical context. They possess highly sensitive transducers able to perform detection of a wide range of nucleic acid-based biomarkers without the need of any label or marker. These optical biosensor platforms are very versatile, allowing the incorporation of an almost limitless range of biorecognition probes precisely and robustly adhered to the sensor surface by covalent surface chemistry approaches. In addition, their application can be further enhanced by their combination with different processes, thanks to their integration with complex and automated microfluidic systems, facilitating the development of multiplexed and user-friendly platforms. The objective of this work is to provide a comprehensive synopsis of cutting-edge analytical strategies based on these label-free optical biosensors able to deal with the drawbacks related to DNA and RNA detection, from single point mutations assays and epigenetic alterations, to bacterial infections. Several plasmonic and silicon photonic-based biosensors are described together with their most recent applications in this area. We also identify and analyse the main challenges faced when attempting to harness this technology and how several innovative approaches introduced in the last years manage those issues, including the use of new biorecognition probes, surface functionalization approaches, signal amplification and enhancement strategies, as well as, sophisticated microfluidic solutions.
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Affiliation(s)
- Cesar S. Huertas
- Integrated Photonics and Applications Centre, School of Engineering, Royal Melbourne Institute of Technology University, Melbourne, VIC, Australia
| | - Olalla Calvo-Lozano
- Nanobiosensors and Bioanalytical Applications Group, Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC and the Barcelona Institute of Science and Technology, CIBER-BBN, Barcelona, Spain
| | - Arnan Mitchell
- Integrated Photonics and Applications Centre, School of Engineering, Royal Melbourne Institute of Technology University, Melbourne, VIC, Australia
| | - Laura M. Lechuga
- Nanobiosensors and Bioanalytical Applications Group, Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC and the Barcelona Institute of Science and Technology, CIBER-BBN, Barcelona, Spain
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48
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Houghton PJ, Kurmasheva RT. Challenges and Opportunities for Childhood Cancer Drug Development. Pharmacol Rev 2019; 71:671-697. [PMID: 31558580 PMCID: PMC6768308 DOI: 10.1124/pr.118.016972] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cancer in children is rare with approximately 15,700 new cases diagnosed in the United States annually. Through use of multimodality therapy (surgery, radiation therapy, and aggressive chemotherapy), 70% of patients will be "cured" of their disease, and 5-year event-free survival exceeds 80%. However, for patients surviving their malignancy, therapy-related long-term adverse effects are severe, with an estimated 50% having chronic life-threatening toxicities related to therapy in their fourth or fifth decade of life. While overall intensive therapy with cytotoxic agents continues to reduce cancer-related mortality, new understanding of the molecular etiology of many childhood cancers offers an opportunity to redirect efforts to develop effective, less genotoxic therapeutic options, including agents that target oncogenic drivers directly, and the potential for use of agents that target the tumor microenvironment and immune-directed therapies. However, for many high-risk cancers, significant challenges remain.
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Affiliation(s)
- Peter J Houghton
- Greehey Children's Cancer Research Institute, University of Texas Health, San Antonio, Texas
| | - Raushan T Kurmasheva
- Greehey Children's Cancer Research Institute, University of Texas Health, San Antonio, Texas
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Abstract
Malignant melanoma is the most aggressive and notorious skin cancer, and metastatic disease is associated with very poor long-term survival outcomes. Although metastatic melanoma patients with oncogenic mutations in the BRAF gene initially respond well to the treatment with specific BRAF inhibitors, most of them will eventually develop resistance to this targeted therapy. As a highly conserved catabolic process, autophagy is responsible for the maintenance of cellular homeostasis and cell survival, and is involved in multiple diseases, including cancer. Recent study results have indicated that autophagy might play a decisive role in the resistance to BRAF inhibitors in BRAF-mutated melanomas. In this review, we will discuss how autophagy is up-regulated by BRAF inhibitors, and how autophagy induces the resistance to these agents.
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50
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Zaman A, Wu W, Bivona TG. Targeting Oncogenic BRAF: Past, Present, and Future. Cancers (Basel) 2019; 11:E1197. [PMID: 31426419 PMCID: PMC6721448 DOI: 10.3390/cancers11081197] [Citation(s) in RCA: 137] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 08/13/2019] [Accepted: 08/13/2019] [Indexed: 12/20/2022] Open
Abstract
Identifying recurrent somatic genetic alterations of, and dependency on, the kinase BRAF has enabled a "precision medicine" paradigm to diagnose and treat BRAF-driven tumors. Although targeted kinase inhibitors against BRAF are effective in a subset of mutant BRAF tumors, resistance to the therapy inevitably emerges. In this review, we discuss BRAF biology, both in wild-type and mutant settings. We discuss the predominant BRAF mutations and we outline therapeutic strategies to block mutant BRAF and cancer growth. We highlight common mechanistic themes that underpin different classes of resistance mechanisms against BRAF-targeted therapies and discuss tumor heterogeneity and co-occurring molecular alterations as a potential source of therapy resistance. We outline promising therapy approaches to overcome these barriers to the long-term control of BRAF-driven tumors and emphasize how an extensive understanding of these themes can offer more pre-emptive, improved therapeutic strategies.
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Affiliation(s)
- Aubhishek Zaman
- Department of Medicine, University of California, San Francisco, CA 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158, USA
| | - Wei Wu
- Department of Medicine, University of California, San Francisco, CA 94143, USA
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158, USA
| | - Trever G Bivona
- Department of Medicine, University of California, San Francisco, CA 94143, USA.
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158, USA.
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