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Golivi Y, Kumari S, Farran B, Alam A, Peela S, Nagaraju GP. Small molecular inhibitors: Therapeutic strategies for pancreatic cancer. Drug Discov Today 2024; 29:104053. [PMID: 38849028 DOI: 10.1016/j.drudis.2024.104053] [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: 03/30/2024] [Revised: 05/21/2024] [Accepted: 05/29/2024] [Indexed: 06/09/2024]
Abstract
Pancreatic cancer (PC), a disease with high heterogeneity and a dense stromal microenvironment, presents significant challenges and a bleak prognosis. Recent breakthroughs have illuminated the crucial interplay among RAS, epidermal growth factor receptor (EGFR), and hedgehog pathways in PC progression. Small molecular inhibitors have emerged as a potential solution with their advantages of oral administration and the ability to target intracellular and extracellular sites effectively. However, despite the US FDA approving over 100 small-molecule targeted antitumor drugs, challenges such as low response rates and drug resistance persist. This review delves into the possibility of using small molecules to treat persistent or spreading PC, highlighting the challenges and the urgent need for a diverse selection of inhibitors to develop more effective treatment strategies.
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Affiliation(s)
- Yuvasri Golivi
- Department of Bioscience and Biotechnology, Banasthali University, Banasthali, RJ 304 022, India
| | - Seema Kumari
- Cancer Biology Laboratory, Department of Biochemistry and Bioinformatics, GIS, GITAM, Visakhapatnam, Andhra Pradesh 530045, India
| | - Batoul Farran
- Department of Hematology and Oncology, Henry Ford Health, Detroit, MI 48202, USA
| | - Afroz Alam
- Department of Bioscience and Biotechnology, Banasthali University, Banasthali, RJ 304 022, India
| | - Sujatha Peela
- Department of Biotechnology, Dr. B. R. Ambedkar University, Srikakulam, Andhra Pradesh, 532001, India
| | - Ganji Purnachandra Nagaraju
- Department of Hematology and Oncology, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35233, USA.
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Deiana C, Agostini M, Brandi G, Giovannetti E. The trend toward more target therapy in pancreatic ductal adenocarcinoma. Expert Rev Anticancer Ther 2024; 24:525-565. [PMID: 38768098 DOI: 10.1080/14737140.2024.2357802] [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: 12/19/2023] [Accepted: 05/16/2024] [Indexed: 05/22/2024]
Abstract
INTRODUCTION Despite the considerable progress made in cancer treatment through the development of target therapies, pancreatic ductal adenocarcinoma (PDAC) continues to exhibit resistance to this category of drugs. As a result, chemotherapy combination regimens remain the primary treatment approach for this aggressive cancer. AREAS COVERED In this review, we provide an in-depth analysis of past and ongoing trials on both well-known and novel targets that are being explored in PDAC, including PARP, EGFR, HER2, KRAS, and its downstream and upstream pathways (such as RAF/MEK/ERK and PI3K/AKT/mTOR), JAK/STAT pathway, angiogenesis, metabolisms, epigenetic targets, claudin, and novel targets (such as P53 and plectin). We also provide a comprehensive overview of the significant trials for each target, allowing a thorough glimpse into the past and future of target therapy. EXPERT OPINION The path toward implementing a target therapy capable of improving the overall survival of PDAC is still long, and it is unlikely that a monotherapy target drug will fulfill a meaningful role in addressing the complexity of this cancer. Thus, we discuss the future direction of target therapies in PDAC, trying to identify the more promising target and combination treatments, with a special focus on the more eagerly awaited ongoing trials.
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Affiliation(s)
- Chiara Deiana
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Margherita Agostini
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giovanni Brandi
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, The Netherlands
- Cancer Pharmacology Lab, Associazione Italiana per la Ricerca sul Cancro (AIRC) Start-Up Unit, Fondazione Pisana per la Scienza, Pisa, San Giuliano, Italy
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Adamopoulos C, Cave DD, Papavassiliou AG. Inhibition of the RAF/MEK/ERK Signaling Cascade in Pancreatic Cancer: Recent Advances and Future Perspectives. Int J Mol Sci 2024; 25:1631. [PMID: 38338909 PMCID: PMC10855714 DOI: 10.3390/ijms25031631] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/22/2024] [Accepted: 01/26/2024] [Indexed: 02/12/2024] Open
Abstract
Pancreatic cancer represents a formidable challenge in oncology, primarily due to its aggressive nature and limited therapeutic options. The prognosis of patients with pancreatic ductal adenocarcinoma (PDAC), the main form of pancreatic cancer, remains disappointingly poor with a 5-year overall survival of only 5%. Almost 95% of PDAC patients harbor Kirsten rat sarcoma virus (KRAS) oncogenic mutations. KRAS activates downstream intracellular pathways, most notably the rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling axis. Dysregulation of the RAF/MEK/ERK pathway is a crucial feature of pancreatic cancer and therefore its main components, RAF, MEK and ERK kinases, have been targeted pharmacologically, largely by small-molecule inhibitors. The recent advances in the development of inhibitors not only directly targeting the RAF/MEK/ERK pathway but also indirectly through inhibition of its regulators, such as Src homology-containing protein tyrosine phosphatase 2 (SHP2) and Son of sevenless homolog 1 (SOS1), provide new therapeutic opportunities. Moreover, the discovery of allele-specific small-molecule inhibitors against mutant KRAS variants has brought excitement for successful innovations in the battle against pancreatic cancer. Herein, we review the recent advances in targeted therapy and combinatorial strategies with focus on the current preclinical and clinical approaches, providing critical insight, underscoring the potential of these efforts and supporting their promise to improve the lives of patients with PDAC.
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Affiliation(s)
- Christos Adamopoulos
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Donatella Delle Cave
- Institute of Genetics and Biophysics ‘Adriano Buzzati-Traverso’, CNR, 80131 Naples, Italy
| | - Athanasios G. Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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Singh S, Kaushik AC, Gupta H, Jhinjharia D, Sahi S. Identification of Prognostic Markers and Potential Therapeutic Targets using Gene Expression Profiling and Simulation Studies in Pancreatic Cancer. Curr Comput Aided Drug Des 2024; 20:955-973. [PMID: 37711100 DOI: 10.2174/1573409920666230914100826] [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: 04/28/2023] [Revised: 07/07/2023] [Accepted: 08/08/2023] [Indexed: 09/16/2023]
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) has a 5-year relative survival rate of less than 10% making it one of the most fatal cancers. A lack of early measures of prognosis, challenges in molecular targeted therapy, ineffective adjuvant chemotherapy, and strong resistance to chemotherapy cumulatively make pancreatic cancer challenging to manage. OBJECTIVE The present study aims to enhance understanding of the disease mechanism and its progression by identifying prognostic biomarkers, potential drug targets, and candidate drugs that can be used for therapy in pancreatic cancer. METHODS Gene expression profiles from the GEO database were analyzed to identify reliable prognostic markers and potential drug targets. The disease's molecular mechanism and biological pathways were studied by investigating gene ontologies, KEGG pathways, and survival analysis to understand the strong prognostic power of key DEGs. FDA-approved anti-cancer drugs were screened through cell line databases, and docking studies were performed to identify drugs with high affinity for ARNTL2 and PIK3C2A. Molecular dynamic simulations of drug targets ARNTL2 and PIK3C2A in their native state and complex with nilotinib were carried out for 100 ns to validate their therapeutic potential in PDAC. RESULTS Differentially expressed genes that are crucial regulators, including SUN1, PSMG3, PIK3C2A, SCRN1, and TRIAP1, were identified. Nilotinib as a candidate drug was screened using sensitivity analysis on CCLE and GDSC pancreatic cancer cell lines. Molecular dynamics simulations revealed the underlying mechanism of the binding of nilotinib with ARNTL2 and PIK3C2A and the dynamic perturbations. It validated nilotinib as a promising drug for pancreatic cancer. CONCLUSION This study accounts for prognostic markers, drug targets, and repurposed anti-cancer drugs to highlight their usefulness for translational research on developing novel therapies. Our results revealed potential and prospective clinical applications in drug targets ARNTL2, EGFR, and PI3KC2A for pancreatic cancer therapy.
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Affiliation(s)
- Samvedna Singh
- School of Biotechnology, Gautam Buddha University, Greater Noida, India
| | | | - Himanshi Gupta
- School of Biotechnology, Gautam Buddha University, Greater Noida, India
| | - Divya Jhinjharia
- School of Biotechnology, Gautam Buddha University, Greater Noida, India
| | - Shakti Sahi
- School of Biotechnology, Gautam Buddha University, Greater Noida, India
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Huang Y, Gong P, Su L, Zhang M. Cuproptosis-related lncRNA scoring system to predict the clinical outcome and immune landscape in pancreatic adenocarcinoma. Sci Rep 2023; 13:20870. [PMID: 38012210 PMCID: PMC10682027 DOI: 10.1038/s41598-023-47223-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 11/10/2023] [Indexed: 11/29/2023] Open
Abstract
Cuproptosis is a recently discovered novel programmed cell death pathway that differs from traditional programmed cell death and has an important role in cancer and immune regulation. Long noncoding RNA (lncRNA) is considered new potential prognostic biomarkers in pancreatic adenocarcinoma (PAAD). However, the prognostic role and immune landscape of cuproptosis-related lncRNA in PAAD remain unclear. The transcriptome and clinical data of PAAD were obtained from The Cancer Genome Atlas (TCGA) database. Cuproptosis-related lncRNA was identified using Pearson correlation analysis. The optimal lncRNA was screened by Cox and the Least Absolute Shrinkage and Selection Operator (LASSO) regression mode, and for the construction of risk scoring system. PAAD patients were divided into high- and low-risk groups according to the risk score. Clinicopathological parameter correlation analysis, univariate and multivariate Cox regression, time-dependent receiver operating characteristic (ROC) curves, and nomogram were performed to evaluate the model. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to explore differences in biological function between different risk groups. Single-sample gene set enrichment analysis (ssGSEA) and Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm were used to analyze the differences in tumor immune microenvironment (TIME) in different risk groups of PAAD. Additionally, the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was used to predict immunotherapy response and identify potential immune beneficiaries. Immune checkpoints and tumor mutation burden (TMB) were also systematically analyzed. Finally, drug sensitivity analysis was used to explore the reactivity of different drugs in high- and low-risk groups to provide a reference for the selection of precise therapeutic drugs. Six cuproptosis-related lncRNAs (AL117335.1, AC044849.1, AL358944.1, ZNF236-DT, Z97832.2, and CASC8) were used to construct risk model. Survival analysis showed that overall survival and progression-free survival in the low-risk group were better than those in the high-risk group, and it is suitable for PAAD patients with different clinical characteristics. Univariate and multifactorial Cox regression analysis showed that risk score was an independent prognostic factor in PAAD patients. ROC analysis showed that the AUC values of the risk score in 1 year, 3 years and 5 years were 0.707,0.762 and 0.880, respectively. Nomogram showed that the total points of PAAD patients at 1 year, 3 years, and 5 years were 0.914,0.648, and 0.543. GO and KEGG analyses indicated that the differential genes in the high- and low-risk groups were associated with tumor proliferation and metastasis and immune regulatory pathway. Immune correlation analysis showed that the amount of pro-inflammatory cells, including CD8+ T cells, was significantly higher in the low-risk group than in the high-risk group, and the expression of immune checkpoint genes, including PD-1 and CTLA-4, was increased in the low-risk group. TIDE analysis suggests that patients in the low-risk group may benefit from immunotherapy. Finally, there was significant variability in multiple chemotherapeutic and targeted drugs across the risk groups, which informs our clinical drug selection. Our cuproptosis-related lncRNA scoring system (CRLss) could predict the clinical outcome and immune landscape of PAAD patients, identify the potential beneficiaries of immunotherapy, and provide a reference for precise therapeutic drug selection.
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Affiliation(s)
- Yi Huang
- Oncology Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ping Gong
- Internal Medicine Department of Oncology, Anhui Wannan Rehabilitation Hospital (The Fifth People's Hospital of Wuhu), Wuhu, China
| | - Li Su
- Oncology Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Mei Zhang
- Oncology Department of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
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Lin J, Lu F, Wu Y, Huang H, Pan Y. The cellular trajectories of tumor-associated macrophages decipher the heterogeneity of pancreatic cancer. Funct Integr Genomics 2023; 23:343. [PMID: 37991591 DOI: 10.1007/s10142-023-01266-y] [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: 10/04/2023] [Revised: 10/27/2023] [Accepted: 11/06/2023] [Indexed: 11/23/2023]
Abstract
Emerging evidence indicates that the interactions and dynamic changes among tumor-associated macrophages (TAMs) are pivotal in molding the tumor microenvironment (TME), thereby influencing diverse clinical outcomes. However, the potential clinical ramifications of these evolutionary shifts in tumor-associated macrophages within pancreatic adenocarcinoma (PAAD) remain largely unexamined. Single-cell RNA sequencing (scRNA-seq) data were retrieved from the Tumor Immune Single-cell Hub. The Seurat and Monocle algorithms were employed to elucidate the progression of TAMs, using non-negative matrix factorization (NMF) to determine molecular classifications. Subsequently, the prognosis, biological characteristics, genomic modifications, and immune landscape across various clusters were interpreted. Furthermore, the sensitivity of potential therapeutic drugs between subtypes was predicted. Cellular experiments were conducted to explore the function of the NR1H3 gene in pancreatic cancer. These experiments encompassed gene knockdown, proliferation assessment, clone formation evaluation, transwell examination, and apoptosis analysis. Trajectory gene expression analysis of tumor-associated macrophages identified three disparate clusters, each associated with different clinical outcomes Compared to clusters C1 and C2, cluster C3 is seemingly at a less advanced pathological stage and associates with a relatively favorable prognosis. Further investigation revealed pronounced genetic instability in cluster C2, whereas cluster C3 demonstrated notable genetic stability. Cluster C1, characterized as "immune-hot," exhibits an abundance of immune cells and elevated immune checkpoint expression, suggesting its suitability for immunotherapy. Furthermore, several potential therapeutic agents have been pinpointed, potentially facilitating the clinical application of these insights. Cell assays indicated that NR1H3 knockdown markedly induced apoptosis and suppressed clonogenesis, migration, and proliferation of pancreatic cancer cells in the PTAU-8988 and PANC-1 cell lines. Overall, our study discerned three clusters with unique characteristics, defined by the evolution of TAMs. We propose customized therapeutic strategies for patients within these specific clusters to improve clinical outcomes and optimize clinical management.
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Affiliation(s)
- Jiajing Lin
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, People's Republic of China
| | - Fengchun Lu
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, People's Republic of China
| | - Yuwei Wu
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, People's Republic of China
| | - Heguang Huang
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, People's Republic of China.
| | - Yu Pan
- Department of General Surgery, Fujian Medical University Union Hospital, No. 29 Xinquan Road, Fuzhou, 350001, People's Republic of China.
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Zhen DB, Safyan RA, Konick EQ, Nguyen R, Prichard CC, Chiorean EG. The role of molecular testing in pancreatic cancer. Therap Adv Gastroenterol 2023; 16:17562848231171456. [PMID: 37197396 PMCID: PMC10184226 DOI: 10.1177/17562848231171456] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 04/06/2023] [Indexed: 05/19/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is highly aggressive and has few treatment options. To personalize therapy, it is critical to delineate molecular subtypes and understand inter- and intra-tumoral heterogeneity. Germline testing for hereditary genetic abnormalities is recommended for all patients with PDA and somatic molecular testing is recommended for all patients with locally advanced or metastatic disease. KRAS mutations are present in 90% of PDA, while 10% are KRAS wild type and are potentially targetable with epidermal growth factor receptor blockade. KRASG12C inhibitors have shown activity in G12C-mutated cancers, and novel G12D and pan-RAS inhibitors are in clinical trials. DNA damage repair abnormalities, germline or somatic, occur in 5-10% of patients and are likely to benefit from DNA damaging agents and maintenance therapy with poly-ADP ribose polymerase inhibitors. Fewer than 1% of PDA harbor microsatellite instability high status and are susceptible to immune checkpoint blockade. Albeit very rare, occurring in <1% of patients with KRAS wild-type PDAs, BRAF V600E mutations, RET and NTRK fusions are targetable with cancer agnostic Food and Drug Administration-approved therapies. Genetic, epigenetic, and tumor microenvironment targets continue to be identified at an unprecedented pace, enabling PDA patients to be matched to targeted and immune therapeutics, including antibody-drug conjugates, and genetically engineered chimeric antigen receptor or T-cell receptor - T-cell therapies. In this review, we highlight clinically relevant molecular alterations and focus on targeted strategies that can improve patient outcomes through precision medicine.
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Affiliation(s)
- David B. Zhen
- University of Washington School of Medicine, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Rachael A. Safyan
- University of Washington School of Medicine, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Eric Q. Konick
- University of Washington, School of Medicine Seattle, WA, USA
| | - Ryan Nguyen
- University of Washington, School of Medicine Seattle, WA, USA
| | | | - E. Gabriela Chiorean
- University of Washington School of Medicine, Fred Hutchinson Cancer Center, 825 Eastlake Avenue East, LG-465, Seattle, WA 98109, USA Fred Hutchinson
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Ebrahimi N, Fardi E, Ghaderi H, Palizdar S, Khorram R, Vafadar R, Ghanaatian M, Rezaei-Tazangi F, Baziyar P, Ahmadi A, Hamblin MR, Aref AR. Receptor tyrosine kinase inhibitors in cancer. Cell Mol Life Sci 2023; 80:104. [PMID: 36947256 PMCID: PMC11073124 DOI: 10.1007/s00018-023-04729-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/31/2023] [Accepted: 02/13/2023] [Indexed: 03/23/2023]
Abstract
Targeted therapy is a new cancer treatment approach, involving drugs that particularly target specific proteins in cancer cells, such as receptor tyrosine kinases (RTKs) which are involved in promoting growth and proliferation, Therefore inhibiting these proteins could impede cancer progression. An understanding of RTKs and the relevant signaling cascades, has enabled the development of many targeted drug therapies employing RTK inhibitors (RTKIs) some of which have entered clinical application. Here we discuss RTK structures, activation mechanisms and functions. Moreover, we cover the potential effects of combination drug therapy (including chemotherapy or immunotherapy agents with one RTKI or multiple RTKIs) especially for drug resistant cancers.
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Affiliation(s)
- Nasim Ebrahimi
- Genetics Division, Department of Cell and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran
| | - Elmira Fardi
- Medical Branch, Islamic Azad University of Tehran, Tehran, Iran
| | - Hajarossadat Ghaderi
- Laboratory of Regenerative and Medical Innovation, Pasteur Institute of Iran, Tehran, Iran
| | - Sahar Palizdar
- Division of Microbiology, Faculty of Basic Sciences, Islamic Azad University of Tehran East Branch, Tehran, Iran
| | - Roya Khorram
- Bone and Joint Diseases Research Center, Department of Orthopedic Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Vafadar
- Department of Orthopeadic Surgery, Kerman University of Medical Sciences, Kerman, Iran
| | - Masoud Ghanaatian
- Master 1 Bio-Santé-Parcours Toulouse Graduate School of Cancer, Ageing and Rejuvenation (CARe), Université Toulouse III-Paul Sabatier, Toulouse, France
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Payam Baziyar
- Department of Molecular and Cell Biology, Faculty of Basic Science, Uinversity of Mazandaran, Babolsar, Iran
| | - Amirhossein Ahmadi
- Department of Biological Science and Technology, Faculty of Nano and Bio Science and Technology, Persian Gulf University, Bushehr, 75169, Iran.
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028, South Africa.
| | - Amir Reza Aref
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
- Translational Medicine Group, Xsphera Biosciences, 6 Tide Street, Boston, MA, 02210, USA.
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Shetu SA, James N, Rivera G, Bandyopadhyay D. Molecular Research in Pancreatic Cancer: Small Molecule Inhibitors, Their Mechanistic Pathways and Beyond. Curr Issues Mol Biol 2023; 45:1914-1949. [PMID: 36975494 PMCID: PMC10047141 DOI: 10.3390/cimb45030124] [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: 01/01/2023] [Revised: 02/06/2023] [Accepted: 02/21/2023] [Indexed: 03/04/2023] Open
Abstract
Pancreatic enzymes assist metabolic digestion, and hormones like insulin and glucagon play a critical role in maintaining our blood sugar levels. A malignant pancreas is incapable of doing its regular functions, which results in a health catastrophe. To date, there is no effective biomarker to detect early-stage pancreatic cancer, which makes pancreatic cancer the cancer with the highest mortality rate of all cancer types. Primarily, mutations of the KRAS, CDKN2A, TP53, and SMAD4 genes are responsible for pancreatic cancer, of which mutations of the KRAS gene are present in more than 80% of pancreatic cancer cases. Accordingly, there is a desperate need to develop effective inhibitors of the proteins that are responsible for the proliferation, propagation, regulation, invasion, angiogenesis, and metastasis of pancreatic cancer. This article discusses the effectiveness and mode of action at the molecular level of a wide range of small molecule inhibitors that include pharmaceutically privileged molecules, compounds under clinical trials, and commercial drugs. Both natural and synthetic small molecule inhibitors have been counted. Anti-pancreatic cancer activity and related benefits of using single and combined therapy have been discussed separately. This article sheds light on the scenario, constraints, and future aspects of various small molecule inhibitors for treating pancreatic cancer-the most dreadful cancer so far.
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Affiliation(s)
- Shaila A. Shetu
- Department of Chemistry, The University of Texas Rio Grande Valley, 1201 West University Drive, Edinburg, TX 78539, USA
| | - Nneoma James
- Department of Chemistry, The University of Texas Rio Grande Valley, 1201 West University Drive, Edinburg, TX 78539, USA
| | - Gildardo Rivera
- Laboratorio de Biotecnología Farmacéutica, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Reynosa 88710, Mexico
| | - Debasish Bandyopadhyay
- Department of Chemistry, The University of Texas Rio Grande Valley, 1201 West University Drive, Edinburg, TX 78539, USA
- School of Earth Environment & Marine Sciences (SEEMS), The University of Texas Rio Grande Valley, 1201 West University Drive, Edinburg, TX 78539, USA
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Mao T, Zhang X, Xu H, Zhang X, Ge W, Li S, Ma J, Yue M, Xue S, Cui J, Wang L. HDACs/mTOR inhibitor synergizes with pyrotinib in HER2-positive pancreatic cancer through degradation of mutant P53. Cancer Cell Int 2022; 22:380. [PMID: 36457011 PMCID: PMC9714091 DOI: 10.1186/s12935-022-02807-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 11/24/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC), as a highly lethal malignancy with high mortality, lacks of effective treatment. Canonical therapeutic targets in PDAC demand further verification among which HER2 receptor tyrosine kinase inhibitor pyrotinib as treatment targets has not be decided. METHODS Anti-PDAC efficacy of pyrotinib was evaluated both in vitro and in vivo using both cell lines and patient-derived xenografts. By screening a large-scale library of 1453 compounds, we identified HDACs/mTOR inhibitor 1 as a promising candidate to synergize with pyrotinib. The combination therapy was evaluated in vitro and in vivo in multiple cell lines and animal models. Furthermore, RNA-seq analysis was performed to reveal the latent molecular mechanism of combination therapy. RESULTS In our study, pyrotinib monotherapy was found to be inefficient to anti-PDAC which exhibited limited anti-proliferation effect in vitro and in vivo. Through therapy combined with HDACs/mTOR inhibitor 1, pyrotinib triggered intense apoptosis in PDAC both in cell lines and animal models. Mechanistic analyses revealed that mutant P53 degradation mediated by HDAC inhibition synergized with HER2 and mTOR inhibition. CONCLUSIONS In conclusion, identification of HDACs/mTOR inhibitor as a synergistic inhibitor, provides a potent therapeutic strategy that targets HER2-positive pancreatic cancer.
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Affiliation(s)
- Tiebo Mao
- grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related GenesDepartment of OncologySchool of Medicine, Shanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University, Shanghai, China
| | - Xiaofei Zhang
- grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related GenesDepartment of OncologySchool of Medicine, Shanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University, Shanghai, China
| | - Haiyan Xu
- grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related GenesDepartment of OncologySchool of Medicine, Shanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University, Shanghai, China
| | - Xiao Zhang
- grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related GenesDepartment of OncologySchool of Medicine, Shanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University, Shanghai, China
| | - Weiyu Ge
- grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related GenesDepartment of OncologySchool of Medicine, Shanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University, Shanghai, China
| | - Shumin Li
- grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related GenesDepartment of OncologySchool of Medicine, Shanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University, Shanghai, China
| | - Jingyu Ma
- grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related GenesDepartment of OncologySchool of Medicine, Shanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University, Shanghai, China
| | - Ming Yue
- grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related GenesDepartment of OncologySchool of Medicine, Shanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University, Shanghai, China
| | - Shengbai Xue
- grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related GenesDepartment of OncologySchool of Medicine, Shanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University, Shanghai, China
| | - Jiujie Cui
- grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related GenesDepartment of OncologySchool of Medicine, Shanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University, Shanghai, China
| | - Liwei Wang
- grid.16821.3c0000 0004 0368 8293State Key Laboratory of Oncogenes and Related GenesDepartment of OncologySchool of Medicine, Shanghai Cancer InstituteRenji HospitalShanghai Jiao Tong University, Shanghai, China
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Rudloff U. Emerging kinase inhibitors for the treatment of pancreatic ductal adenocarcinoma. Expert Opin Emerg Drugs 2022; 27:345-368. [PMID: 36250721 PMCID: PMC9793333 DOI: 10.1080/14728214.2022.2134346] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 08/22/2022] [Accepted: 10/06/2022] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Pancreatic cancer is one of the deadliest solid organ cancers. In the absence of specific warning symptoms pancreatic cancer is diagnosed notoriously late. Current systemic chemotherapy regimens extend survival by a mere few months. With the advances in genetic, proteomic, and immunological profiling there is strong rationale to test kinase inhibitors to improve outcome. AREAS COVERED This review article provides a comprehensive summary of approved treatments and past, present, and future developments of kinase inhibitors in pancreatic cancer. Emerging roles of protein kinase inhibitors are discussed in the context of the unique stroma, the lack of high-prevalence therapeutic targets and rapid emergence of acquired resistance, novel immuno-oncology kinase targets, and recent medicinal chemistry advances. EXPERT OPINION Due to the to-date frequent failure of protein kinase inhibitors indiscriminately administered to unselected pancreatic cancer patients, there is a shift toward the development of these agents in molecularly defined subgroups which are more likely to respond. The development of accurate biomarkers to select patients who are the best candidates based on a detailed understanding of mechanism of action, pro-survival roles, and mediation of resistance of targeted kinases will be critical for the future development of protein kinase inhibitors in this disease.
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Affiliation(s)
- Udo Rudloff
- Rare Tumor Initiative, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
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12
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Su K, Peng Y, Yu H. Development of a Prognostic Model Based on Pyroptosis-Related Genes in Pancreatic Adenocarcinoma. DISEASE MARKERS 2022; 2022:9141117. [PMID: 35677632 PMCID: PMC9169203 DOI: 10.1155/2022/9141117] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 05/12/2022] [Accepted: 05/19/2022] [Indexed: 11/17/2022]
Abstract
Background The importance of pyroptosis in tumorigenesis and cancer progression is becoming increasingly apparent. However, the efficacy of using pyroptosis-related genes (PRGs) in predicting the prognosis of pancreatic adenocarcinoma (PAAD) patients is unknown. Methods This investigation used two databases to obtain expression data for PAAD patients. Differentially expressed PRGs (DEPRGs) were identified between PAAD and control samples. Several bioinformatic approaches were used to analyze the biological functions of DEPRGs and to identify prognostic DERPGs. A miRNA-prognostic DEPRG-transcription factor (TF) regulatory network was created via the miRNet online tool. A risk score model was created after each patient's risk score was calculated. The microenvironments of the low- and high-risk groups were assessed using xCell, the expression of immune checkpoints was determined, and gene set variation analysis (GSVA) was performed. Finally, the efficacy of certain potential drugs was predicted using the pRRophetic algorithm, and the results in the high- and low-risk groups were compared. Results A total of 13 DEPRGs were identified between PAAD and control samples. Functional enrichment analysis showed that the DEPRGs had a close relationship with inflammation. In univariate and multivariate Cox regression analyses, GSDMC, IRF1, and PLCG1 were identified as prognostic biomarkers in PAAD. The results of the miRNA-prognostic DEPRG-TF regulatory network showed that GSDMC, IRF1, and PLCG1 were regulated by both specific and common miRNAs and TFs. Based on the risk score and other independent prognostic indicators, a nomogram with a good ability to predict the survival of PAAD patients was developed. By evaluating the tumor microenvironment, we observed that the immune and metabolic microenvironments of the two groups were substantially different. In addition, individuals in the low-risk group were more susceptible to axitinib and camptothecin, whereas lapatinib might be preferred for patients in the high-risk group. Conclusion Our study revealed the prognostic value of PRGs in PAAD and created a reliable model for predicting the prognosis of PAAD patients. Our findings will benefit the prognostication and treatment of PAAD patients.
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Affiliation(s)
- Kaifeng Su
- Medical Faculty of Ludwig-Maximilians-University of Munich, University Hospital of LMU Munich, Munich, Germany
| | - Yang Peng
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Haochen Yu
- Medical Faculty of Ludwig-Maximilians-University of Munich, University Hospital of LMU Munich, Munich, Germany
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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13
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Kang BW, Chau I. Emerging agents for metastatic pancreatic cancer: spotlight on early phase clinical trials. Expert Opin Investig Drugs 2021; 30:1089-1107. [PMID: 34727804 DOI: 10.1080/13543784.2021.1995354] [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: 02/08/2023]
Abstract
INTRODUCTION Despite the recent development of new chemotherapeutic regimens and combination strategies, metastatic pancreatic cancer (mPC) still shows only a modest response to conventional cytotoxic agents. However, several novel therapeutic agents targeting the unique features of mPC are showing promise in clinical trials. AREA COVERED This article reviews the current state of development of new agents targeting various systems and molecular pathways. We searched PubMed and clinicaltrials.gov in September 2021 with a special focus on ongoing early phase clinical trials to identify the promising therapeutic strategies for mPC. EXPERT OPINION Extensive tumor heterogeneity, complex tumor microenvironment, genetic alterations of the oncogenic signaling pathways, metabolic dysregulation, and a low immunogenicity are hurdles for current treatment approaches. Ongoing research efforts strive to overcome these hurdles and are showing some promising early results.
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Affiliation(s)
- Byung Woog Kang
- Department of Oncology/Hematology, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Kyungpook National University, Daegu, Republic of Korea
| | - Ian Chau
- Department of Medicine, Royal Marsden Hospital, London, Surrey, UK
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14
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Hani U, Osmani RAM, Siddiqua A, Wahab S, Batool S, Ather H, Sheraba N, Alqahtani A. A systematic study of novel drug delivery mechanisms and treatment strategies for pancreatic cancer. J Drug Deliv Sci Technol 2021. [DOI: 10.1016/j.jddst.2021.102539] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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15
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Al-Share B, Hammad N, Diab M. Pancreatic adenocarcinoma: molecular drivers and the role of targeted therapy. Cancer Metastasis Rev 2021; 40:355-371. [PMID: 33398620 DOI: 10.1007/s10555-020-09948-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 12/15/2020] [Indexed: 01/05/2023]
Abstract
Prognosis from pancreatic ductal adenocarcinoma (PDAC) continues to be poor despite the many efforts channeled to improve its management. Although the mainstay treatment is still traditional chemotherapy, recent advances highlighted a promising potential for targeted therapy in the management of this disease. Those advances emphasize the significance of timely genomic profiling of tumor tissue as well as germline testing of patients to identify potential markers of targeted therapy. While targeted therapy is reserved for a relatively small subset of patients with PDAC, ongoing research is uncovering additional markers, and targeted agents, that will hopefully translate to better outcomes for patients.
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Affiliation(s)
- Bayan Al-Share
- Department of Oncology, Wayne State University, Karmanos Cancer Institute, Detroit, MI, USA
| | - Nour Hammad
- Department of Oncology, Ascension Providence Hospital and Medical Center/Michigan State University/Collage of Human Medicine, Southfield, MI, USA
| | - Maria Diab
- Department of Oncology, Emory University, Atlanta, GA, USA.
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16
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Lin Z, Lu S, Xie X, Yi X, Huang H. Noncoding RNAs in drug-resistant pancreatic cancer: A review. Biomed Pharmacother 2020; 131:110768. [PMID: 33152930 DOI: 10.1016/j.biopha.2020.110768] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 09/17/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is the fourth-leading cause of cancer-related deaths and is expected to be the second-leading cause of cancer-related deaths in Europe and the United States by 2030. The high fatality rate of pancreatic cancer is ascribed to untimely diagnosis, early metastasis and limited responses to both chemotherapy and radiotherapy. Although gemcitabine, 5-fluorouracil and some other drugs can profoundly improve patient prognosis, most pancreatic cancer patients eventually develop drug resistance, leading to poor clinical outcomes. The underlying mechanisms of pancreatic cancer drug resistance are complicated and inconclusive. Interestingly, accumulating evidence has demonstrated that different noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), play a crucial role in pancreatic cancer resistance to chemotherapy reagents. In this paper, we systematically summarize the molecular mechanism underlying the influence of ncRNAs on the generation and development of drug resistance in pancreatic cancer and discuss the potential role of ncRNAs as prognostic markers and new therapeutic targets for pancreatic cancer.
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Affiliation(s)
- Zhengjun Lin
- Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China.
| | - Shiyao Lu
- Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China.
| | - Xubin Xie
- Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China.
| | - Xuyang Yi
- Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China.
| | - He Huang
- Department of Histology and Embryology, Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, China; State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, School of Pre-Clinical Medicine/ Second Affiliated Hospital, Xinjiang Medical University, Urumqi, Xinjiang, 830011, China.
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17
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Taghizadeh H, Müllauer L, Mader RM, Schindl M, Prager GW. Applied precision medicine in metastatic pancreatic ductal adenocarcinoma. Ther Adv Med Oncol 2020; 12:1758835920938611. [PMID: 32699558 PMCID: PMC7357054 DOI: 10.1177/1758835920938611] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 06/05/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Metastatic pancreatic ductal adenocarcinoma (mPDAC) bears a dismal prognosis due to the limited activity of systemic chemotherapy. In our platform for precision medicine, we aim to offer molecular-guided treatments to patients without further standard therapy options. METHODS In this single center, real-world retrospective analysis of our platform, we describe the molecular-based therapy approaches used in all 50 patients diagnosed with therapy-refractory mPDAC. A molecular portrait of the tumor specimens was created by next-generation sequencing, immunohistochemistry (IHC), microsatellite instability (MSI) testing, and fluorescence in situ hybridization. RESULTS In total, we detected 123 mutations in 50 patients. The five most frequent mutations were KRAS (n = 40; 80%), TP53 (n = 29; 58%), CDKN2A (n = 8; 16%), SMAD4 (n = 4; 8%), and NOTCH1 (n = 4; 8%), which together accounted for 40.2% of all mutations. Two patients had gene fusions, namely, TBL1XR1-PIK3CA and EIF3E-RSPO2. IHC detected expression of EGFR, phosphorylated mTOR, and PTEN in 36 (72%), 33 (66%), and 17 patients (34%), respectively. For 14 (28%) of the 50 patients, a targeted therapy was suggested based on the identified molecular targets. The recommended treatments included the mTOR inhibitor everolimus (n = 3), pembrolizumab (n = 3), palbociclib (n = 2), nintedanib (n = 2), and cetuximab, crizotinib, tamoxifen, and the combination of lapatinib and trastuzumab, in one patient each.Finally, five patients received the recommended therapy. Four patients died due to disease progression before radiological assessment. One patient was treated with nintedanib and achieved stable disease for 6 months. CONCLUSION Based on our observations, precision medicine approaches are feasible and implementable in clinical routine and may provide molecular-based therapy recommendations for mPDAC.
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Affiliation(s)
- Hossein Taghizadeh
- Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Austria
- Comprehensive Cancer Center Vienna, Austria
| | - Leonhard Müllauer
- Comprehensive Cancer Center Vienna, Austria
- Clinical Institute of Pathology, Medical University Vienna, Vienna, Austria
| | - Robert M. Mader
- Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Austria
- Comprehensive Cancer Center Vienna, Austria
| | - Martin Schindl
- Comprehensive Cancer Center Vienna, Austria
- Department of Surgery, Division of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Gerald W. Prager
- Department of Medicine I, Clinical Division of Oncology, Comprehensive Cancer Center Vienna, Precision Cancer Medicine Unit, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria
- Comprehensive Cancer Center Vienna, Austria
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18
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Sun J, Russell CC, Scarlett CJ, McCluskey A. Small molecule inhibitors in pancreatic cancer. RSC Med Chem 2020; 11:164-183. [PMID: 33479626 PMCID: PMC7433757 DOI: 10.1039/c9md00447e] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 12/09/2019] [Indexed: 12/17/2022] Open
Abstract
Pancreatic cancer (PC), with a 5 year survival of <7%, is one of the most fatal of all human cancers. The highly aggressive and metastatic character of this disease poses a challenge that current therapies are failing, despite significant efforts, to meet. This review examines the current status of the 35 small molecule inhibitors targeting pancreatic cancer in clinical trials and the >50 currently under investigation. These compounds inhibit biological targets spanning protein kinases, STAT3, BET, HDACs and Bcl-2 family proteins. Unsurprisingly, protein kinase inhibitors are overrepresented. Some trials show promise; a phase I combination trial of vorinostat 11 and capecitabine 17 gave a median overall survival (MoS) of 13 months and a phase II study of pazopanib 15 showed a MoS of 25 months. The current standard of care for metastatic pancreatic ductal adenocarcinoma, fluorouracil/folic acid (5-FU, Adrucil®), and gemcitabine (GEMZAR®) afforded a MoS of 23 and 23.6 months (EPAC-3 study), respectively. In patients who can tolerate the FOLFIRINOX regime, this is becoming the standard of treatment with a MoS of 11.1 months. Clinical study progress has been slow with limited improvement in patient survival relative to gemcitabine 1 monotherapy. A major cause of low PC survival is the late stage of diagnosis, occurring in patients who consider typical early stage warning signs of aches and pains normal. The selection of patients with specific disease phenotypes, the use of improved efficient drug combinations, the identification of biomarkers to specific cancer subtypes and more effective designs of investigation have improved outcomes. To move beyond the current dire condition and paucity of PC treatment options, determination of the best regimes and new treatment options is a challenge that must be met. The reasons for poor PC prognosis have remained largely unchanged for 20 years. This is arguably a consequence of significant changes in the drug discovery landscape, and the increasing pressure on academia to deliver short term 'media' friendly short-term news 'bites'. PC research sits at a pivotal point. Perhaps the greatest challenge is enacting a culture change that recognises that major breakthroughs are a result of blue sky, truly innovative and curiosity driven research.
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Affiliation(s)
- Jufeng Sun
- Chemistry , School of Environmental & Life Sciences , The University of Newcastle , Newcastle , Callaghan , NSW 2308 , Australia . ; ; Tel: +61 249216486
- Medicinal Chemistry , School of Pharmacy , Binzhou Medical University , Yantai , 264003 , China
| | - Cecilia C Russell
- Chemistry , School of Environmental & Life Sciences , The University of Newcastle , Newcastle , Callaghan , NSW 2308 , Australia . ; ; Tel: +61 249216486
| | - Christopher J Scarlett
- Applied Sciences , School of Environmental & Life Sciences , The University of Newcastle , Ourimbah NSW 2258 , Australia
| | - Adam McCluskey
- Chemistry , School of Environmental & Life Sciences , The University of Newcastle , Newcastle , Callaghan , NSW 2308 , Australia . ; ; Tel: +61 249216486
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19
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Lakkakula BVKS, Farran B, Lakkakula S, Peela S, Yarla NS, Bramhachari PV, Kamal MA, Saddala MS, Nagaraju GP. Small molecule tyrosine kinase inhibitors and pancreatic cancer-Trials and troubles. Semin Cancer Biol 2019; 56:149-167. [PMID: 30314681 DOI: 10.1016/j.semcancer.2018.09.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 09/18/2018] [Accepted: 09/29/2018] [Indexed: 12/20/2022]
Abstract
Pancreatic cancer (PC) is an aggressive carcinoma and the fourth cause of cancer deaths in Western countries. Although surgery is the most effective therapeutic option for PC, the management of unresectable, locally advanced disease is highly challenging. Our improved understanding of pancreatic tumor biology and associated pathways has led to the development of various treatment modalities that can control the metastatic spread of PC. This review intends to present trials of small molecule tyrosine kinase inhibitors (TKIs) in PC management and the troubles encountered due to inevitable acquired resistance to TKIs.
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Affiliation(s)
| | - Batoul Farran
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA-30322, USA
| | - Saikrishna Lakkakula
- Department of Zoology, Visvodaya Government Degree College, Venkatagiri, AP-524132, India
| | - Sujatha Peela
- Department of Biotechnology, Dr.B.R.Ambedkar University, Srikakulam, Andhra Pradesh, India
| | - Nagendra Sastry Yarla
- Dr. LV Prasad Diagnostics and Research Laboratory, Khairtabad, Hyderabad, AP- 500004, India
| | | | - Mohammad Amjad Kamal
- King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770, Australia; Novel Global Community Educational Foundation, Australia
| | | | - Ganji Purnachandra Nagaraju
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA-30322, USA.
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20
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Tong M, Wang J, Zhang H, Xing H, Wang Y, Fang Y, Pan H, Li D. Efficacy and safety of gemcitabine plus anti-angiogenesis therapy for advanced pancreatic cancer: a systematic review and meta-analysis of clinical randomized phase III trials. J Cancer 2019; 10:968-978. [PMID: 30854103 PMCID: PMC6400798 DOI: 10.7150/jca.26672] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Accepted: 10/28/2018] [Indexed: 01/12/2023] Open
Abstract
Purpose: Pancreatic cancer is a common digestive neoplasm with a high fatality rate. We performed this systematic review and meta-analysis of clinical randomized phase III trials to explore the efficacy and safety of gemcitabine plus anti-angiogenesis therapy versus gemcitabine monotherapy for locally advanced or metastatic pancreatic cancer. Methods: We searched PubMed, Embase and the Cochrane Library to identify eligible studies. Data were collected for the period from January 1, 2000 to August 20, 2018. Hazard ratios (HRs) and odds ratios (ORs) were used as main evaluation parameters. Results: A total of eight eligible studies with 3,586 individuals were included in the present meta-analysis. The results showed that the combination of gemcitabine plus anti-angiogenesis therapy had a significant effect on progression-free survival (HR = 0.92, 95% CI: 0.86 - 1.00, P = 0.04), but led to no significant difference in the overall survival (HR = 0.96, 95% CI: 0.88 - 1.05, P = 0.38). In terms of safety, gemcitabine plus anti-angiogenesis therapy did not increase the rate of grade 3-4 common adverse effects except for hypertension. Conclusions: Although gemcitabine plus anti-angiogenesis therapy might prolong the progression-free survival in locally advanced or metastatic pancreatic cancer, these successful results did not translate into a significant improvement in the overall survival or change in the clinical guidelines.
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Affiliation(s)
- Mengting Tong
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3#, Eastern Qingchun Road, Jianggan District, Hangzhou, Zhejiang, China, 310016.,Second Department of Medical Oncology, The Fourth Affiliated Hospital of Xinjiang Medical University, 116#, Huang He Road, Saybagh District, Urumqi, Xinjiang, China, 830000
| | - Jing Wang
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3#, Eastern Qingchun Road, Jianggan District, Hangzhou, Zhejiang, China, 310016
| | - Hongliang Zhang
- Second Department of Medical Oncology, The Fourth Affiliated Hospital of Xinjiang Medical University, 116#, Huang He Road, Saybagh District, Urumqi, Xinjiang, China, 830000
| | - Haibo Xing
- Intensive Care Department, Xiasha Campus, Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine, 368#, Xiasha Road, Jianggan District, Hangzhou, Zhejiang, China, 310000
| | - Yanling Wang
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3#, Eastern Qingchun Road, Jianggan District, Hangzhou, Zhejiang, China, 310016
| | - Yong Fang
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3#, Eastern Qingchun Road, Jianggan District, Hangzhou, Zhejiang, China, 310016
| | - Hongming Pan
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3#, Eastern Qingchun Road, Jianggan District, Hangzhou, Zhejiang, China, 310016
| | - Da Li
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3#, Eastern Qingchun Road, Jianggan District, Hangzhou, Zhejiang, China, 310016
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21
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Diab M, Azmi A, Mohammad R, Philip PA. Pharmacotherapeutic strategies for treating pancreatic cancer: advances and challenges. Expert Opin Pharmacother 2018; 20:535-546. [PMID: 30592647 DOI: 10.1080/14656566.2018.1561869] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Despite many efforts to improve the outcome of pancreatic ductal adenocarcinoma (PDAC), its prognosis remains poor, which is mostly related to late diagnosis and drug resistance. Improving systemic therapy is considered the major challenge in improving the outcome of this disease. AREAS COVERED This review covers novel chemotherapy and targeted agents in the treatment of PDAC, with a focus on advanced stage disease. EXPERT OPINION Current frontline therapies used in the treatment of patients with PDAC with favorable performance status are gemcitabine (GEM) and nab-paclitaxel or 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). PDAC has a number of genetic mutations that may explain its biological behavior, such as KRAS, p53 and CDK2NA, which occur in more than 90% of cases. Unfortunately, to this day, a specific targeting agent to any of those frequent gene mutations is lacking. Emerging areas of targeted therapies include the DNA repair, stroma, metabolism, and stem cells. Immunotherapy with either vaccines or immune checkpoint inhibitors has not produced any significant improvements in outcome of PDAC. Incorporating different approaches in therapy, including conventional, immunological, and others, is key in offering patients with the best possible care.
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Affiliation(s)
- Maria Diab
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA
| | - Asfar Azmi
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA
| | - Ramzi Mohammad
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA
| | - Philip A Philip
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA.,b Department of Pharmacology, School of Medicine , Wayne State University , Detroit , MI , USA
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22
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Barati Bagherabad M, Afzaljavan F, ShahidSales S, Hassanian SM, Avan A. Targeted therapies in pancreatic cancer: Promises and failures. J Cell Biochem 2018; 120:2726-2741. [PMID: 28703890 DOI: 10.1002/jcb.26284] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 07/11/2018] [Indexed: 12/14/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an incidence rate nearly equal to its mortality rate. The poor prognosis of the disease can be explained by the absence of effective biomarkers for screening and early detection, together with the aggressive behavior and resistance to the currently available chemotherapy. The therapeutic failure can also be attributed to the inter-/intratumor genetic heterogeneity and the abundance of tumor stroma that occupies the majority of the tumor mass. Gemcitabine is used in the treatment of PDAC; however, the response rate is less than 12%. A recent phase III trial revealed that the combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin could be an option for the treatment of metastatic PDAC patients with good performance status, although these approaches can result in high toxicity level. Further investigations are required to develop innovative anticancer agents that either improve gemcitabine activity, within novel combinatorial approaches or acts with a better efficacy than gemcitabine. The aim of the current review is to give an overview of preclinical and clinical studies targeting key dysregulated signaling pathways in PDAC.
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Affiliation(s)
- Matineh Barati Bagherabad
- Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fahimeh Afzaljavan
- Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Soodabeh ShahidSales
- Cancer Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Molecular Medicine group, Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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23
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Park S, Kim D, Wu G, Jung H, Park JA, Kwon HJ, Lee Y. A peptide-CpG-DNA-liposome complex vaccine targeting TM4SF5 suppresses growth of pancreatic cancer in a mouse allograft model. Onco Targets Ther 2018; 11:8655-8672. [PMID: 30584324 PMCID: PMC6284540 DOI: 10.2147/ott.s186606] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Background Patients with pancreatic cancer have a poor prognosis and are usually diagnosed at a late stage. Because TM4SF5 is known to be overexpressed in hepatocellular carcinoma, colon cancer, and pancreatic cancer, it is considered as one of the candidate molecular targets for an anticancer strategies. Purpose The purpose of this study was to evaluate possible utility of TM4SF5 to treat pancreatic cancer using a mouse allograft model. Materials and methods We analyzed expression of TM4SF5 in pancreatic cancer tissues using immunohistochemistry. We established a mouse pancreatic cancer cell line stably expressing TM4SF5 and identified the effect of TM4SF5 expression in vitro. We used the CpG-DNA-peptide-liposome complex as a peptide vaccine and investigated antitumor effects of the vaccine in a mouse model with TM4SF5 expressing pancreatic cells. To investigate the function of produced antibody, we evaluated effects of the anti-TM4SF5 monoclonal antibody in vitro in terms of cell growth and migration properties. Results Immunohistochemical analysis showed that 36.4% of pancreatic cancer tissue samples expressed TM4SF5. Expression of TM4SF5 induced increased cell proliferation and motility in vitro. Injection of the TM4SF5 peptide vaccine induced the production of anti-hTM4SF5 antibodies and reduced the growth of pancreatic tumors in mice established by subcutaneous injection of the TM4SF5-expressing mouse pancreatic cancer cell line. The treatment of TM4SF5-expressing cells with the anti-hTM4SF5 monoclonal antibody reduced cell growth, modulated the expression of the epithelial–mesenchymal transition markers Vimentin and E-cadherin, and decreased cell motility in vitro. Conclusion Our results showed that the TM4SF5 peptide vaccine had a protective effect against pancreatic tumors expressing TM4SF5, and this effect was mediated, at least in part, by the production and suppressive function of the anti-TM4SF5 antibodies. Therefore, we suggest that targeting TM4SF5 could be a novel strategy to prevent or treat pancreatic cancer.
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Affiliation(s)
- Sangkyu Park
- Department of Biochemistry, College of Natural Sciences, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea, .,Biotechnology Research Institute, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea,
| | - Dongbum Kim
- Center for Medical Science Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea,
| | - Guang Wu
- Center for Medical Science Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea, .,School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China,
| | - Harry Jung
- Center for Medical Science Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea,
| | - Jeong-A Park
- Department of Biochemistry, College of Natural Sciences, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea, .,Biotechnology Research Institute, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea,
| | - Hyung-Joo Kwon
- Center for Medical Science Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea, .,Department of Microbiology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
| | - Younghee Lee
- Department of Biochemistry, College of Natural Sciences, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea, .,Biotechnology Research Institute, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea,
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Hua J, Shi S, Liang D, Liang C, Meng Q, Zhang B, Ni Q, Xu J, Yu X. Current status and dilemma of second-line treatment in advanced pancreatic cancer: is there a silver lining? Onco Targets Ther 2018; 11:4591-4608. [PMID: 30122951 PMCID: PMC6084072 DOI: 10.2147/ott.s166405] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Pancreatic cancer remains one of the most lethal malignant diseases worldwide. The majority of patients present with advanced disease and, therefore, need palliative chemotherapy. Some chemotherapeutic regimens have been well established as first-line therapies and have been shown to increase survival; however, almost all patients with advanced pancreatic cancer will experience disease progression after first-line therapy. Nevertheless, many patients who retain good performance status after initial treatment remain good candidates for additional therapy. Historically, few studies have assessed second-line therapy, with most reports representing small phase II trials with variable findings; however, clinical research for second-line treatment has increased in the past decade, and several randomized controlled trials using different regimens have been published. The current literature shows varying results on treatment efficacy and tolerability. Thus, we reviewed the published data on the use of chemotherapy in the second-line setting for the treatment of advanced pancreatic cancer.
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Affiliation(s)
- Jie Hua
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China, ;
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China, ;
- Pancreatic Cancer Institute, Fudan University, Shanghai, People's Republic of China, ;
- Shanghai Pancreatic Cancer Institute, Shanghai, People's Republic of China, ;
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China, ;
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China, ;
- Pancreatic Cancer Institute, Fudan University, Shanghai, People's Republic of China, ;
- Shanghai Pancreatic Cancer Institute, Shanghai, People's Republic of China, ;
| | - Dingkong Liang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China, ;
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China, ;
- Pancreatic Cancer Institute, Fudan University, Shanghai, People's Republic of China, ;
- Shanghai Pancreatic Cancer Institute, Shanghai, People's Republic of China, ;
| | - Chen Liang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China, ;
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China, ;
- Pancreatic Cancer Institute, Fudan University, Shanghai, People's Republic of China, ;
- Shanghai Pancreatic Cancer Institute, Shanghai, People's Republic of China, ;
| | - Qingcai Meng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China, ;
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China, ;
- Pancreatic Cancer Institute, Fudan University, Shanghai, People's Republic of China, ;
- Shanghai Pancreatic Cancer Institute, Shanghai, People's Republic of China, ;
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China, ;
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China, ;
- Pancreatic Cancer Institute, Fudan University, Shanghai, People's Republic of China, ;
- Shanghai Pancreatic Cancer Institute, Shanghai, People's Republic of China, ;
| | - Quanxing Ni
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China, ;
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China, ;
- Pancreatic Cancer Institute, Fudan University, Shanghai, People's Republic of China, ;
- Shanghai Pancreatic Cancer Institute, Shanghai, People's Republic of China, ;
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China, ;
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China, ;
- Pancreatic Cancer Institute, Fudan University, Shanghai, People's Republic of China, ;
- Shanghai Pancreatic Cancer Institute, Shanghai, People's Republic of China, ;
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China, ;
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China, ;
- Pancreatic Cancer Institute, Fudan University, Shanghai, People's Republic of China, ;
- Shanghai Pancreatic Cancer Institute, Shanghai, People's Republic of China, ;
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Kowalewski A, Szylberg Ł, Saganek M, Napiontek W, Antosik P, Grzanka D. Emerging strategies in BRCA-positive pancreatic cancer. J Cancer Res Clin Oncol 2018; 144:1503-1507. [PMID: 29777302 PMCID: PMC6061050 DOI: 10.1007/s00432-018-2666-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 05/14/2018] [Indexed: 12/18/2022]
Abstract
PURPOSE We propose a treatment algorithm for PDAC with particular emphasis on BRCA1 or 2 mutation-positive patients. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest diseases in the United States and Europe. BRCA1 and BRCA2 are among the most common of the known genetic mutations involved in familial PDAC. The optimal chemotherapy regimen to use for BRCA1 or 2 mutation carriers with PDAC is not yet established. As new treatment options emerge, algorithms must balance the need to give the best drugs first with ensuring that there are still beneficial options available for later. METHODS We conducted a review of the literature for data on possible therapies in BRCA-positive and BRCA-negative pancreatic cancer. RESULTS There is accumulating evidence of increased sensitivity to platinum-based therapy and poly-ADP-ribose polymerase inhibitors (PARPi) in BRCA-associated PDAC. There are no studies relating to borderline BRCA-associated PDAC and, therefore, same treatment as for sporadic PDAC seems appropriate. Treatment of unresectable PDAC varies depending on stage of the disease. Patients with BRCA-associated locally advanced PDAC can benefit from targeted therapy with PARPi (olaparib) as a second-line therapy after antimetabolite treatment failure. Patients with unresectable metastatic BRCA-positive PDAC may benefit from platinum-based therapy. CONCLUSION Targeted therapies are shifting the treatment paradigms and increasing survival for patients with PDAC, a group that used to have a grim prognosis.
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Affiliation(s)
- Adam Kowalewski
- Department of Clinical Pathology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland
| | - Łukasz Szylberg
- Department of Clinical Pathology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland
- Department of Pathology, Military Clinical Hospital, Powstańców Warszawy Str. 5, 85-681, Bydgoszcz, Poland
| | - Michał Saganek
- Department of Clinical Pathology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland
| | - Wojciech Napiontek
- Department of Clinical Pathology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland.
| | - Paulina Antosik
- Department of Clinical Pathology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland
| | - Dariusz Grzanka
- Department of Clinical Pathology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094, Bydgoszcz, Poland
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Hajatdoost L, Sedaghat K, Walker EJ, Thomas J, Kosari S. Chemotherapy in Pancreatic Cancer: A Systematic Review. ACTA ACUST UNITED AC 2018; 54:medicina54030048. [PMID: 30344279 PMCID: PMC6122094 DOI: 10.3390/medicina54030048] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 07/05/2018] [Indexed: 02/06/2023]
Abstract
Background and Aim: Pancreatic cancer is one of the most fatal cancers. Cytotoxic chemotherapy remains the mainstream treatment for unresectable pancreatic cancer. This systematic review evaluated and compared the overall survival (OS) and progression-free survival (PFS) outcomes obtained from recent phase 2 and 3 clinical trials of pancreatic cancer chemotherapy. Materials and methods: Thirty-two studies were included and compared based on chemotherapy agents or combinations used. Additionally, outcomes of first-line versus second-line chemotherapy in pancreatic cancer were compared. Results: In studies that investigated the treatments in adjuvant settings, the highest OS reported was for S-1 in patients, who received prior surgical resection (46.5 months). In neoadjuvant settings, the combination of gemcitabine, docetaxel, and capecitabine prior to the surgical resection had promising outcomes (OS of 32.5 months). In non-adjuvant settings, the highest OS reported was for the combination of temsirolimus plus bevacizumab (34.0 months). Amongst studies that investigated second-line treatment, the highest OS reported was for the combination of gemcitabine plus cisplatin (35.5 months), then temsirolimus plus bevacizumab (34.0 months). Conclusions: There is a need to develop further strategies besides chemotherapy to improve the outcomes in pancreatic cancer treatment. Future studies should consider surgical interventions, combination chemotherapy, and individualized second-line treatment based on the prior chemotherapy.
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Affiliation(s)
- Leva Hajatdoost
- Department of Pharmaceutical Sciences, Baha'i Institute for Higher Education (BIHE), Tehran 11369, Iran.
| | - Keyvan Sedaghat
- Department of Pharmaceutical Sciences, Baha'i Institute for Higher Education (BIHE), Tehran 11369, Iran.
| | - Erin J Walker
- Discipline of Pharmacy, Faculty of Health, University of Canberra, Bruce, Canberra 2617 ACT, Australia.
| | - Jackson Thomas
- Discipline of Pharmacy, Faculty of Health, University of Canberra, Bruce, Canberra 2617 ACT, Australia.
| | - Sam Kosari
- Discipline of Pharmacy, Faculty of Health, University of Canberra, Bruce, Canberra 2617 ACT, Australia.
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27
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Neoptolemos JP, Kleeff J, Michl P, Costello E, Greenhalf W, Palmer DH. Therapeutic developments in pancreatic cancer: current and future perspectives. Nat Rev Gastroenterol Hepatol 2018; 15:333-348. [PMID: 29717230 DOI: 10.1038/s41575-018-0005-x] [Citation(s) in RCA: 781] [Impact Index Per Article: 111.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The overall 5-year survival for pancreatic cancer has changed little over the past few decades, and pancreatic cancer is predicted to be the second leading cause of cancer-related mortality in the next decade in Western countries. The past few years, however, have seen improvements in first-line and second-line palliative therapies and considerable progress in increasing survival with adjuvant treatment. The use of biomarkers to help define treatment and the potential of neoadjuvant therapies also offer opportunities to improve outcomes. This Review brings together information on achievements to date, what is working currently and where successes are likely to be achieved in the future. Furthermore, we address the questions of how we should approach the development of pancreatic cancer treatments, including those for patients with metastatic, locally advanced and borderline resectable pancreatic cancer, as well as for patients with resected tumours. In addition to embracing newer strategies comprising genomics, stromal therapies and immunotherapies, conventional approaches using chemotherapy and radiotherapy still offer considerable prospects for greater traction and synergy with evolving concepts.
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Affiliation(s)
- John P Neoptolemos
- Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
| | - Jörg Kleeff
- Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany. .,Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
| | - Patrick Michl
- Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Eithne Costello
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - William Greenhalf
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Daniel H Palmer
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
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28
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Targeted therapies in the management of locally advanced and metastatic pancreatic cancer: a systematic review. Oncotarget 2018; 9:21613-21627. [PMID: 29765563 PMCID: PMC5940404 DOI: 10.18632/oncotarget.25085] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 03/12/2018] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer has a dismal prognosis particularly in patients presenting with unresectable tumors. We performed a bibliometric analysis of clinical trials for pancreatic cancer conducted between 2014-2016 focusing on patients that presented with unresectable (locally advanced or metastatic) tumors. We discuss a range of studies that employed FOLFIRINOX, the gemcitabine + nab-paclitaxel combination and studies that used molecularly-targeted therapy. Major areas of focus have been dual targeting of EGFR and VEGFR, immunotherapy or a multimodal approach – combining chemotherapy with radiotherapy. We also point out the need for molecular selection for low prevalence subtypes. Key insights sourced from these pivotal trials should improve clinical outcomes for this devastating cancer.
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29
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Bai E, Yang L, Xiang Y, Hu W, Li C, Lin J, Dai X, Liang G, Jin R, Zhao C. L61H46 shows potent efficacy against human pancreatic cancer through inhibiting STAT3 pathway. Cancer Manag Res 2018; 10:565-581. [PMID: 29606890 PMCID: PMC5868586 DOI: 10.2147/cmar.s159090] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. The poor prognosis of this disease highlights the urgent need to develop more effective therapies. Activation of the STAT3 represents a potential drug target for pancreatic cancer therapy. Currently, clinically available small-molecule inhibitors targeting STAT3 are lacking. Methods Through bioassay screening and molecular docking, we identified a small molecule L61H46 that can potently target constitutive STAT3 signaling and kill human pancreatic cancer cells in vitro and in vivo. Results L61H46 effectively reduced colony formation and the viability of pancreatic cancer cells in a dose-dependent manner with half-maximal inhibitory concentration (IC50) values in the range between 0.86 and 2.83 µM. L61H46 significantly inhibited STAT3 phosphorylation (Tyr705) and the subsequent nucleus translocation but did not downregulate STAT1 phosphorylation. Moreover, L61H46 demonstrated a potent activity in suppressing pancreatic tumor growth in BXPC-3 xenograft model in vivo. Furthermore, L61H46 showed no signs of adverse effects on liver, heart, and kidney cells in vivo. Conclusion Collectively, our results suggest that L61H46 could be further optimized into a highly potent STAT3 inhibitor for the treatment of pancreatic cancer.
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Affiliation(s)
- Encheng Bai
- Chemical Biology Research Center, School of Pharmaceutical Sciences.,Department of Epidemiology, First Affiliated Hospital
| | - Lehe Yang
- Chemical Biology Research Center, School of Pharmaceutical Sciences
| | - Youqun Xiang
- Department of Epidemiology, First Affiliated Hospital
| | - Wanle Hu
- Department of Coloproctology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China
| | - Caleb Li
- Dublin Coffman High School, Dublin, OH
| | - Jiayuh Lin
- Department of Biochemistry and Molecular Biology, University of Maryland Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Xuanxuan Dai
- Department of Epidemiology, First Affiliated Hospital
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Sciences
| | - Rong Jin
- Department of Epidemiology, First Affiliated Hospital
| | - Chengguang Zhao
- Chemical Biology Research Center, School of Pharmaceutical Sciences
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Zhang Y, Yang C, Cheng H, Fan Z, Huang Q, Lu Y, Fan K, Luo G, Jin K, Wang Z, Liu C, Yu X. Novel agents for pancreatic ductal adenocarcinoma: emerging therapeutics and future directions. J Hematol Oncol 2018; 11:14. [PMID: 29386069 PMCID: PMC5793409 DOI: 10.1186/s13045-017-0551-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Accepted: 12/28/2017] [Indexed: 02/08/2023] Open
Abstract
A poor prognosis of pancreatic ductal adenocarcinoma (PDAC) associated with chemoresistance has not changed for the past three decades. A multidisciplinary diagnosis followed by surgery and chemo(radiation)therapy is the main treatment approach. However, gemcitabine- and 5-fluorouracil-based therapies did not present satisfying outcomes. Novel regimens targeting pancreatic cancer cells, the tumor microenvironment, and immunosuppression are emerging. Biomarkers concerning the treatment outcome and patient selection are being discovered in preclinical or clinical studies. Combination therapies of classic chemotherapeutic drugs and novel agents or novel therapeutic combinations might bring hope to the dismal prognosis for PDAC patients.
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Affiliation(s)
- Yiyin Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - Chao Yang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - He Cheng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - Zhiyao Fan
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - Qiuyi Huang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - Yu Lu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - Kun Fan
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - Guopei Luo
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - Kaizhou Jin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - Zhengshi Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China
| | - Chen Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China.
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China.
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China.
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China.
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China.
- Shanghai Pancreatic Cancer Institute, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China.
- Pancreatic Cancer Institute, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China.
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Albiol-Chiva J, Esteve-Romero J, Peris-Vicente J. Development of a method to determine axitinib, lapatinib and afatinib in plasma by micellar liquid chromatography and validation by the European Medicines Agency guidelines. J Chromatogr B Analyt Technol Biomed Life Sci 2018; 1074-1075:61-69. [PMID: 29331859 DOI: 10.1016/j.jchromb.2017.12.034] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 12/19/2017] [Accepted: 12/28/2017] [Indexed: 12/11/2022]
Abstract
A method based on micellar liquid chromatography to quantify the tyrosine kinase inhibitors axitinib, lapatinib and afatinib in plasma is reported. The sample pretreatment was a simple 1/5-dilution in a pure micellar solution, filtration and direct injection, without requiring extraction or purification steps. The three drugs were resolved from the matrix in 17min, using an aqueous solution of 0.07M sodium dodecyl sulfate - 6.0% 1-pentanol, buffered at pH7 with 0.01M phosphate salt as mobile phase, running under isocratic mode at 1mL/min through a C18 column. The detection was performed by absorbance at 260nm. An accurate mathematical relationship was established between the retention factor of each drug and the surfactant/organic solvent concentration in the mobile phase, achieved with a limited number of experiments, in order to optimize these factors. A binding behavior of the analytes face to the micelles was found out. The method was successfully validated by the guidelines of the European Medicines Agency in terms of: selectivity, linearity (r2>0.9995), calibration range (0.5 to 10mg/L), limit of detection (0.2mg/L), carry-over effect, accuracy (-8.1 to +6.9%), precision (<13.8%), dilution integrity, matrix effect, stability and robustness. The procedure was found reliable, practical, economic, accessible, short-time, easy-to-handle, inexpensive, environmental-friendly, safe, useful for the analysis of many samples per day. Finally, the method was applied to the analysis of incurred, using quality control samples in the same analytical run, with adequate results. Therefore, it can be implementable for routine analysis in clinical laboratories.
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Affiliation(s)
- Jaume Albiol-Chiva
- Departament de Química Física i Analítica, Universitat Jaume I, 12071 Castelló, Spain
| | - Josep Esteve-Romero
- Departament de Química Física i Analítica, Universitat Jaume I, 12071 Castelló, Spain
| | - Juan Peris-Vicente
- Departament de Química Física i Analítica, Universitat Jaume I, 12071 Castelló, Spain; Departament de Química Analítica, Universitat de València, Av/Doctor Moliner 50, 46100 Burjassot, Valencia, Spain.
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32
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Abstract
The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases plays an important role in the biology of many cancers. In breast and gastrointestinal cancer, and at lower rates also in additional tumor types, HER2 and its homo- or heterodimerization with HER1 or HER3 are essential for cancer cell growth and survival. Breast cancer patients overexpressing HER2 have a more aggressive course of their disease. The poor prognosis associated with HER2 overexpression can be substantially improved by adding HER2-targeted therapy to standard of care using the monoclonal antibody trastuzumab. Lapatinib, an oral dual tyrosine kinase inhibitor, blocks HER1 and HER2 tyrosine kinase activity by binding to the ATP-binding site of the receptor's intracellular domain, resulting in inhibition of tumor cell growth. Lapatinib is generally well tolerated with diarrhea being the most common adverse effect. However, although being mainly of mild to moderate severity, interruption or discontinuation of treatment has been reported in a substantial proportion of patients in clinical trials. In 2007, lapatinib has been approved in combination with capecitabine in patients with advanced HER2-positive breast cancer upon progressive disease following standard therapy with anthracyclines, taxanes, and trastuzumab. In 2013, the approval was extended to a chemotherapy-free combination with trastuzumab for patients with metastatic HER2-positive, hormone receptor-negative breast cancer progressing on prior trastuzumab and chemotherapy. Since 2010, lapatinib is approved in combination with letrozole in the treatment of postmenopausal women with advanced HER2- and hormone receptor-positive breast cancer. In contrast, in first-line cytotoxic-based therapy of both early and advanced HER2-positive breast cancer, data from clinical trials did not provide evidence of additional benefit of lapatinib compared to trastuzumab. Moreover, over the past few years, novel HER2-targeted drugs, either alone or as a combined anti-HER2 approach, have been extensively evaluated, demonstrating a more favorable outcome. Also, neither in first- nor second-line treatment of advanced gastric cancer, lapatinib has been proven to be superior compared to trastuzumab as hitherto standard of care HER2 blockade. Therefore, lapatinib has become somewhat less important in patients with HER2-positive breast cancer during the past 10 years since its first introduction. Nevertheless, consideration of treatment with lapatinib appears to be reasonable in selected patients not only in the approved applications but also beyond, and further indications such as HER2-positive refractory metastatic colorectal cancer may arise in future. Also, lapatinib may have distinct advantages over antibodies in targeting truncated HER2 and crossing the blood-brain barrier. Finally, the favorable cardiac toxicity profile of lapatinib makes it an attractive alternative to trastuzumab-based regimens in patients at risk for cardiac events.
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Affiliation(s)
- Minna Voigtlaender
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tanja Schneider-Merck
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Glaxo Smith Kline, Hamburg, Germany
| | - Martin Trepel
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. .,Department of Hematology and Oncology, Interdisciplinary Cancer Center Augsburg, Augsburg Medical Center, Stenglinstr. 2, 86156, Augsburg, Germany.
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Li CM, Liu ZC, Bao YT, Sun XD, Wang LL. Extraordinary response of metastatic pancreatic cancer to apatinib after failed chemotherapy: A case report and literature review. World J Gastroenterol 2017; 23:7478-7488. [PMID: 29151702 PMCID: PMC5685854 DOI: 10.3748/wjg.v23.i41.7478] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 09/13/2017] [Accepted: 09/26/2017] [Indexed: 02/06/2023] Open
Abstract
Chemotherapy has limited efficacy in the treatment of advanced and metastatic pancreatic cancer (PC), and has serious side effects. The development of novel effective agents, especially targeted therapy, is essential for patients with PC. We present a 58-year-old Chinese woman initially diagnosed with locally advanced PC. As the disease progressed to Stage IV, the patient was unable to tolerate chemotherapy after the fourth-line treatment. She was then treated with apatinib, a novel and highly selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 and achieved a progression-free-survival of 7 mo. All drug-related side effects were well controlled with medication. To the best of our knowledge, this is the first case of PC which responded to apatinib. Considering this remarkable response, apatinib may be a promising agent in the treatment of PC. We also reviewed the literature on chemotherapy and targeted therapy, especially the anti-angiogenesis therapy for patients with PC, and investigated the effect of apatinib in other solid tumors as well.
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Affiliation(s)
- Cheng-Ming Li
- School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan 250101, Shandong Province, China
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China
| | - Zhi-Chao Liu
- School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan 250101, Shandong Province, China
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China
| | - You-Ting Bao
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China
- Department of Oncology, Weifang Medical University, Weifang 261042, Shandong Province, China
| | - Xin-Dong Sun
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China
| | - Lin-Lin Wang
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China
- School of Medicine, Shandong University, Jinan 250012, Shandong Province, China
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Chiaravalli M, Reni M, O'Reilly EM. Pancreatic ductal adenocarcinoma: State-of-the-art 2017 and new therapeutic strategies. Cancer Treat Rev 2017; 60:32-43. [DOI: 10.1016/j.ctrv.2017.08.007] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Revised: 08/13/2017] [Accepted: 08/14/2017] [Indexed: 12/18/2022]
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Ruess DA, Görgülü K, Wörmann SM, Algül H. Pharmacotherapeutic Management of Pancreatic Ductal Adenocarcinoma: Current and Emerging Concepts. Drugs Aging 2017; 34:331-357. [PMID: 28349415 DOI: 10.1007/s40266-017-0453-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma is a devastating malignancy, which is the result of late diagnosis, aggressive disease, and a lack of effective treatment options. Thus, pancreatic ductal adenocarcinoma is projected to become the second leading cause of cancer-related death by 2030. This review summarizes recent developments of oncological therapy in the palliative setting of metastatic pancreatic ductal adenocarcinoma. It further compiles novel targets and therapeutic approaches as well as promising treatment combinations, which are presently in preclinical evaluation, covering several aspects of the hallmarks of cancer. Finally, challenges to the implementation of an individualized therapy approach in the context of precision medicine are discussed.
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Affiliation(s)
- Dietrich A Ruess
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.
| | - Kivanc Görgülü
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany
| | - Sonja M Wörmann
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany
| | - Hana Algül
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.
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Adamska A, Domenichini A, Falasca M. Pancreatic Ductal Adenocarcinoma: Current and Evolving Therapies. Int J Mol Sci 2017; 18:E1338. [PMID: 28640192 PMCID: PMC5535831 DOI: 10.3390/ijms18071338] [Citation(s) in RCA: 412] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 06/01/2017] [Accepted: 06/13/2017] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), which constitutes 90% of pancreatic cancers, is the fourth leading cause of cancer-related deaths in the world. Due to the broad heterogeneity of genetic mutations and dense stromal environment, PDAC belongs to one of the most chemoresistant cancers. Most of the available treatments are palliative, with the objective of relieving disease-related symptoms and prolonging survival. Currently, available therapeutic options are surgery, radiation, chemotherapy, immunotherapy, and use of targeted drugs. However, thus far, therapies targeting cancer-associated molecular pathways have not given satisfactory results; this is due in part to the rapid upregulation of compensatory alternative pathways as well as dense desmoplastic reaction. In this review, we summarize currently available therapies and clinical trials, directed towards a plethora of pathways and components dysregulated during PDAC carcinogenesis. Emerging trends towards targeted therapies as the most promising approach will also be discussed.
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Affiliation(s)
- Aleksandra Adamska
- Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia.
| | - Alice Domenichini
- Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia.
| | - Marco Falasca
- Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia.
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Kim MJ, Kim MS, Kim SJ, An S, Park J, Park H, Lee JH, Song KB, Hwang DW, Chang S, Kim KP, Jeong SY, Kim SC, Hong SM. Establishment and characterization of 6 novel patient-derived primary pancreatic ductal adenocarcinoma cell lines from Korean pancreatic cancer patients. Cancer Cell Int 2017; 17:47. [PMID: 28435405 PMCID: PMC5397831 DOI: 10.1186/s12935-017-0416-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 04/10/2017] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinomas are among the most malignant neoplasms and have very poor prognosis. Our understanding of various cancers has recently improved the survival of patients with cancer, except for pancreatic cancers. Establishment of primary cancer cell lines of pancreatic ductal adenocarcinomas will be useful for understanding the molecular mechanisms of this disease. METHODS Eighty-one surgically resected pancreatic ductal adenocarcinomas were collected. Six novel pancreatic cancer cell lines, AMCPAC01-06, were established and histogenetic characteristics were compared with their matched tissues. The clinicopathologic and molecular characteristics of the cell lines were investigated by KRAS and TP53 sequencing or SMAD4 and p53 immunohistochemistry. Xenografts using AMCPAC cell lines were established. RESULTS From the 81 pancreatic ductal adenocarcinomas, six (7.4% success rate) patient-derived primary cell lines were established. The six AMCPAC cell lines showed various morphologies and exhibited a wide range of doubling times. AMCPAC cell lines contained mutant KRAS in codons 12, 13, or 61 and TP53 in exon 5 as well as showed aberrant p53 (5 overexpression and 1 total loss) or DPC4 (all 6 intact) expression. AMCPAC cell lines demonstrated homology for the KRAS mutation and p53 expression compared with matched primary cancer tissues, but showed heterogeneous DPC4 expression patterns. CONCLUSIONS The novel AMCPAC01-06 cell lines established in this study may contribute to the understanding of pancreatic ductal adenocarcinomas. Trial registration Retrospectively registered.
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Affiliation(s)
- Mi-Ju Kim
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Min-Sun Kim
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Sung Joo Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505 Republic of Korea
| | - Soyeon An
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505 Republic of Korea
| | - Jin Park
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Hosub Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505 Republic of Korea
| | - Jae Hoon Lee
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505 Republic of Korea
| | - Ki-Byung Song
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505 Republic of Korea
| | - Dae Wook Hwang
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505 Republic of Korea
| | - Suhwan Chang
- Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, South Korea
- Department of Physiology, University of Ulsan College of Medicine, Seoul, South Korea
| | - Kyu-pyo Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Seong-Yun Jeong
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
- Center for Advancing Cancer Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Song Cheol Kim
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505 Republic of Korea
| | - Seung-Mo Hong
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505 Republic of Korea
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Neuzillet C, Rousseau B, Kocher H, Bourget P, Tournigand C. Unravelling the pharmacologic opportunities and future directions for targeted therapies in gastro-intestinal cancers Part 1: GI carcinomas. Pharmacol Ther 2017; 174:145-172. [PMID: 28223233 DOI: 10.1016/j.pharmthera.2017.02.028] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the molecular biology of cancer cell has led to the therapeutic revolution of targeted therapies, i.e. monoclonal antibodies or small molecule inhibitors directed against proteins that are specifically overexpressed or mutated in cancer cells. These agents being more specific to cancer cells were expected to be less toxic than cytotoxic agents. Targeted agents have provided clinical benefit in many GI cancer types. For example, antiangiogenics and anti-EGFR therapies have significantly improved survival of patients affected by metastatic colorectal cancer and have deeply changed the therapeutic strategy in this disease. However, their effects have sometimes been disappointing, due to intrinsic or acquired resistance mechanisms (e.g., RAS mutation for anti-EGFR therapies), or to an activity restricted to some tumour settings (e.g., lack of activity in other cancer types, or on the microscopic residual disease in adjuvant setting). Many studies are negative in overall population but positive in some specific patient subgroups (e.g., trastuzumab in HER2-positive gastric cancer), illustrating the importance of patient selection and early identification of predictive biomarkers of response to these therapies. We propose a comprehensive two-part review providing a panoramic approach of the successes and failures of targeted agents in GI cancers to unravel the pharmacologic opportunities and future directions for these agents in GI oncology. In this first part, we will focus on adenocarcinomas and squamous cell carcinomas, for which targeted therapies are mostly used in combination with chemotherapy.
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Affiliation(s)
- Cindy Neuzillet
- INSERM UMR1149, Bichat-Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 46 rue Henri Huchard, 75018 Paris, and 100 boulevard du Général Leclerc, 92110 Clichy, France; Department of Medical Oncology, Henri Mondor University Hospital, AP-HP, Paris Est Créteil University (UPEC), 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France; Tumour Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom; Barts and The London HPB Centre, The Royal London Hospital, Whitechapel, London, E1 1BB, United Kingdom.
| | - Benoît Rousseau
- Department of Medical Oncology, Henri Mondor University Hospital, AP-HP, Paris Est Créteil University (UPEC), 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France
| | - Hemant Kocher
- Tumour Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom; Barts and The London HPB Centre, The Royal London Hospital, Whitechapel, London, E1 1BB, United Kingdom
| | - Philippe Bourget
- Department of Clinical Pharmacy, Necker-Enfants Malades University Hospital, 149 Rue de Sèvres, 75015 Paris, France
| | - Christophe Tournigand
- Department of Medical Oncology, Henri Mondor University Hospital, AP-HP, Paris Est Créteil University (UPEC), 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France
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