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Khan A, Sisodiya S, Aftab M, Tanwar P, Hussain S, Gupta V. Mechanisms and Therapeutic Strategies for Endocrine Resistance in Breast Cancer: A Comprehensive Review and Meta-Analysis. Cancers (Basel) 2025; 17:1653. [PMID: 40427153 DOI: 10.3390/cancers17101653] [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: 02/07/2025] [Revised: 03/22/2025] [Accepted: 03/25/2025] [Indexed: 05/29/2025] Open
Abstract
Background: As per recent scenarios, drug resistance is a significant challenge in treating breast cancer for several reasons, such as genetic mutations, altered signaling pathways, and tumor microenvironment. Endocrine resistance is one of the biggest significant barriers to treatment, particularly in hormone receptor-positive (HR+) breast cancers, which depends on estrogen or progesterone signaling for growth. While therapies such as tamoxifen, aromatase inhibitors, and selective estrogen receptor degraders (SERDs) have effectively targeted these pathways, many patients develop resistance, rendering them less effective over time, which is driving a need for innovative therapeutics to treat breast cancer and overcome drug resistance and better treatment outcomes. Recent studies suggest that combining the different therapies, including immunotherapy, targeted therapy, chemotherapy, etc., with endocrine therapy, may bypass the endocrine resistance. Methodology: We conducted a comprehensive systematic review and meta-analysis examining the molecular mechanisms of endocrine resistance and evaluating randomized clinical trial outcomes, overall survival and progression-free survival in endocrine-resistant breast cancer patients treated with endocrine therapy, targeted therapy, immunotherapy, or chemotherapy. Results: We have analyzed 35 randomized clinical trial studies for different therapies along with combination therapy, and our results demonstrated that supplementary or additional therapies in endocrine resistance breast cancer patients have better progression-free and overall survival. Conclusions: The current study has demonstrated that combination therapies may have good survival results and patient outcomes in endocrine resistance. Also, This review sheds light on current challenges in drug resistance and the future direction of cancer treatment through a comprehensive analysis of these emerging treatment approaches to improve patient outcomes.
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Affiliation(s)
- Asiya Khan
- Multidisciplinary Research Unit, Government Institute of Medical Sciences, Greater Noida 201310, India
- Department of Pathology, Government Institute of Medical Sciences, Greater Noida 201310, India
| | - Sandeep Sisodiya
- Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR-National Institute of Cancer Prevention and Research, Ministry of Health and Family Welfare, Government of India, Noida 201301, India
- Symbiosis School of Biological Sciences (SSBS), Symbiosis International (Deemed University) (SIU), Pune 412115, India
| | - Mehreen Aftab
- Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR-National Institute of Cancer Prevention and Research, Ministry of Health and Family Welfare, Government of India, Noida 201301, India
| | - Pranay Tanwar
- Lab Oncology Unit, Dr. B.R.A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Showket Hussain
- Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR-National Institute of Cancer Prevention and Research, Ministry of Health and Family Welfare, Government of India, Noida 201301, India
| | - Vivek Gupta
- Department of Pathology, Government Institute of Medical Sciences, Greater Noida 201310, India
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Jin MY, Yu H, Deng Q, Wang Z, Wang JY, Li HL, Liang H. Virtual screening and molecular dynamics simulation study of ATP-competitive inhibitors targeting mTOR protein. PLoS One 2025; 20:e0319608. [PMID: 40324009 PMCID: PMC12052163 DOI: 10.1371/journal.pone.0319608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 02/04/2025] [Indexed: 05/07/2025] Open
Abstract
In order to explore efficient ATP-competitive mTOR inhibitors and aid the development of targeted anticancer drugs, this study focuses on virtual screening and molecular dynamics simulations. The compounds were sourced from the ChemDiv commercial compound library, and through virtual screening, 50 ligands with favorable binding modes and excellent docking scores were selected from 902,998 compounds. Molecular dynamics simulations, including RMSD (Root Mean Square Deviation) and RMSF (Root Mean Square Fluctuation), were used to further evaluate these 50 ligands. Structural stability, key residue interactions, hydrogen bonding, binding free energy, and other factors were quantitatively and qualitatively analyzed. Top1, top2, and top6, which exhibited outstanding performance, were identified. Simulations revealed that they bind stably in the active region of the mTOR protein, forming hydrogen bonds, π-π interactions, and hydrophobic interactions with key amino acid residues such as VAL-2240 and TRP-2239. This study provides a solid theoretical foundation for the development of mTOR inhibitors. Subsequent efforts will focus on optimizing these compounds, targeting structural adjustments to enhance their biological activity and specificity towards mTOR, thereby achieving more precise targeting and treatment of tumors.
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Affiliation(s)
- Mei-Yu Jin
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Department of Urology, People’s Hospital of Longhua, Shenzhen, China
| | - Hao Yu
- State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, China
| | - Qiong Deng
- Department of Urology, People’s Hospital of Longhua, Shenzhen, China
| | - Zhu Wang
- Department of Urology, People’s Hospital of Longhua, Shenzhen, China
| | - Jie-Yan Wang
- Department of Urology, People’s Hospital of Longhua, Shenzhen, China
| | - Hao-Long Li
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Department of Urology, People’s Hospital of Longhua, Shenzhen, China
| | - Hui Liang
- Department of Urology, People’s Hospital of Longhua, Shenzhen, China
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Liu K, Shi H, Gao L, Ye L, Lu B. Endocervical adenocarcinoma with a micropapillary component: a clinicopathologic analysis in the setting of current WHO classification. Virchows Arch 2025; 486:1011-1021. [PMID: 39579262 DOI: 10.1007/s00428-024-03971-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 10/07/2024] [Accepted: 11/05/2024] [Indexed: 11/25/2024]
Abstract
Our study aimed to investigate the clinicopathologic and molecular features of endocervical adenocarcinoma with a micropapillary component (EAC-MP) in the setting of current classification schema. We investigated 26 EAC-MP from consecutive 511 adenocarcinomas. HER2 status was analyzed by immunohistochemistry and fluorescence in situ hybridization. Four cases were performed with targeted next-generation sequencing (NGS). We found that HPV-associated adenocarcinomas (HPVA) with a micropapillary component (HPVA-MP) (n = 12) had a higher frequency of large tumor size (> 2 cm), Silva pattern C (12/12, 100%), invasion of the deep cervical wall (> 2/3) (8/12, 66.7%), lymphovascular space invasion (LVSI) (11/12, 91.7%), lymph node metastasis (4/11, 36.4%), FIGO stage III/IV (4/12, 33.3%), and HER2 amplification (3/12, 25%, P = 0.015), compared to those without (HPVA-NMP (all P < 0.05). HPV-independent adenocarcinomas (HPVI) with a micropapillary component (HPVI-MP) (n = 14) had LVSI more commonly than those without (HPVI-NMP) (P = 0.033). Survival analysis indicated that HPVA-MP was associated with worse overall survival and recurrence-free survival than HPVA-NMP (P < 0.01). Particularly, in patients with Silva pattern C, HPVA-MP appeared to have more adverse clinical outcomes (P < 0.01). No survival differences were found in HPVI-MP versus HPVI-NMP (P > 0.05). NGS identified significant mutations in STK11, TERT, ERBB2, TP53, PIK3CA, ARID1A, and NTRK2. We conclude that the micropapillary structure is an indicator for unfavorable clinical outcomes in HPVA, and can aid in the prognostic stratification of Silva pattern C EAC. The presence of HER2 amplification and specific gene mutations raise the possibility for targeted therapy in the future.
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Affiliation(s)
- Keyi Liu
- Department of Gynecology & Obstetrics, School of Medicine, Women's Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Haiyan Shi
- Department of Surgical Pathology, School of Medicine, Women's Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Limei Gao
- School of Basic Medicine & Forensic Medicine, Hangzhou Medical College, Hangzhou, Zhejiang Province, China
| | - Lei Ye
- Department of Surgical Pathology, School of Medicine, Women's Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Bingjian Lu
- Department of Surgical Pathology, Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, School of Medicine, Women's Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China.
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Zhao X, Chen C, Feng X, Lei H, Qi L, Zhang H, Xu H, Wan J, Zhang Y, Yang B. Emd-D inhibited ovarian cancer progression via PFKFB4-dependent glycolysis and apoptosis. Chin J Nat Med 2025; 23:431-442. [PMID: 40274346 DOI: 10.1016/s1875-5364(25)60843-0] [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: 12/23/2023] [Revised: 04/11/2024] [Accepted: 04/27/2024] [Indexed: 04/26/2025]
Abstract
Ovarian cancer poses a significant threat to women's health, necessitating effective therapeutic strategies. Emd-D, an emodin derivative, demonstrates enhanced pharmaceutical properties and bioavailability. In this study, Cell Counting Kit 8 (CCK8) assays and Ki-67 staining revealed dose-dependent inhibition of cell proliferation by Emd-D. Migration and invasion experiments confirmed its inhibitory effects on OVHM cells, while flow cytometry analysis demonstrated Emd-D-induced apoptosis. Mechanistic investigations elucidated that Emd-D functions as an inhibitor by directly binding to the glycolysis-related enzyme PFKFB4. This was corroborated by alterations in intracellular lactate and pyruvate levels, as well as glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) expression. PFKFB4 overexpression experiments further supported the dependence of Emd-D on PFKFB4-mediated glycolysis and SRC3/mTORC1 pathway-associated apoptosis. In vivo experiments exhibited reduced xenograft tumor sizes upon Emd-D treatment, accompanied by suppressed glycolysis and increased expression of Bax/Bcl-2 apoptotic proteins within the tumors. In conclusion, our findings demonstrate Emd-D's potential as an anti-ovarian cancer agent through inhibition of the PFKFB4-dependent glycolysis pathway and induction of apoptosis. These results provide a foundation for further exploration of Emd-D as a promising drug candidate for ovarian cancer treatment.
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Affiliation(s)
- Xin Zhao
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin 150081, China
| | - Chao Chen
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Xuefei Feng
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Haoqi Lei
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Lingling Qi
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Hongxia Zhang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Haiying Xu
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Jufeng Wan
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
| | - Yan Zhang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin 150081, China.
| | - Baofeng Yang
- Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases (NKLFZCD), Harbin Medical University, Harbin 150081, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China.
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Nguyen TTH, Mital S. Cost-Effectiveness of Capivasertib as a Second-Line Therapy for Advanced Breast Cancer. PHARMACOECONOMICS 2025; 43:351-361. [PMID: 39630382 DOI: 10.1007/s40273-024-01456-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/06/2024] [Indexed: 02/14/2025]
Abstract
BACKGROUND Capivasertib, a first-in-class AKT inhibitor, was recently approved as a second-line treatment for advanced breast cancer. However, capivasertib is expensive, raising questions over its economic value. This study provides the first evidence on the cost effectiveness of adding capivasertib to endocrine therapy (fulvestrant) for patients with PIK3CA/AKT1/PTEN-altered, hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. METHODS A Markov model was built to compare the costs and effectiveness of three treatment strategies. The first strategy involved adding capivasertib to fulvestrant for all patients, while the second strategy involved adding it for only postmenopausal women. The third strategy involved treatment with fulvestrant alone. Analyses were conducted from a US payer perspective over a lifetime horizon. Costs were measured in 2023 US dollars, and effectiveness was measured in life years (LYs) and quality adjusted life years (QALYs), discounted at 3% per year. One-way sensitivity analyses, probabilistic sensitivity analyses, and scenario analyses were conducted to assess the robustness of results. RESULTS The addition of capivasertib to fulvestrant for all patients was associated with $410,765 higher costs and 1.46 additional quality adjusted life years (QALYs) compared with fulvestrant alone, resulting in an incremental cost effectiveness ratio of $280,854/QALY. The strategy of adding capivasertib for only patients who are postmenopausal was extended dominated, i.e., yielded fewer QALYs at a higher cost per QALY than if capivasertib was added for all patients. These results were found to be robust in sensitivity and scenario analyses. CONCLUSIONS At its current price, our analysis suggests that the addition of capivasertib to fulvestrant as a second line treatment is not cost effective versus fulvestrant alone at a willingness-to-pay threshold of $100,000/QALY. The price of capivasertib will need to be reduced by nearly 70% (to $7000 per cycle) for it to become cost effective.
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Affiliation(s)
- Trang T H Nguyen
- College of Pharmacy, University of Manitoba, 750 McDermot Avenue, Winnipeg, R3E0T5, Canada
| | - Shweta Mital
- College of Pharmacy, University of Manitoba, 750 McDermot Avenue, Winnipeg, R3E0T5, Canada.
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Bahrami N, Abdi M. Knockout of histone deacetylase 8 gene in breast cancer cells may alter the expression pattern of the signaling molecules. Adv Med Sci 2025; 70:27-32. [PMID: 39437892 DOI: 10.1016/j.advms.2024.10.003] [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: 05/02/2024] [Revised: 07/26/2024] [Accepted: 10/18/2024] [Indexed: 10/25/2024]
Abstract
PURPOSE Breast cancer (BC) is the most common cancer diagnosed in the world and it is also the main leading cause of cancer deaths in women. Change in epigenetic mechanisms promotes BC initiation and progression. Histone deacetylase 8 (HDAC8) was found to act as a potential oncogene in different malignancies. For better understanding of the HDAC8 function in BC development, we investigated the effect of HDAC8 deletion on the expression of genes involved in signaling pathways. MATERIALS AND METHODS In this study, CRISPR technology was used to knockout the HDAC8 gene in MDA-MB-468, MDA-MB-231 and MCF-7 cell lines. For this purpose, two gRNAs were designed and cloned into the PX459 vector. The gRNA-containing vectors were transfected into the BC cell lines and then the effect of this deletion on the expression of genes involved in signaling pathway was determined using quantitative real-time PCR (qRT-PCR). RESULTS Analysis of qRT-PCR results showed a reduction in the expression of studied genes in BC cell lines after deletion of the HDAC8 gene compared to untreated controls. Although this decline was not significant for FGF2 and FGFR1 genes, however the mTOR, IGF1R, INSR, VEGFA and VEGFR2 genes showed statistically significant reduction in the studied BC cell lines. In addition, the down-regulation of PDGFC and PDGFRA genes were only significant in the TNBC cell lines. CONCLUSION Overall, our study showed that HDAC8 can exert its oncogenic effects by altering the expression level of molecules involved in some signaling pathways, and inhibiting HDAC8 can revert these effects.
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Affiliation(s)
- Nahid Bahrami
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mohammad Abdi
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran; Department of Clinical Biochemistry, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
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Annoor A, Rahman Marzan M, Iqbal RB, Ferdausi A, Yasmeen A, Tarannum P, John P. Alpelisib-Induced Hyperglycemia in PIK3CA+ Breast Cancer Patients. South Med J 2025; 118:97-101. [PMID: 39883146 DOI: 10.14423/smj.0000000000001791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2025]
Abstract
Alpelisib is a phosphatidylinositol 3-kinase inhibitor approved by the US Food and Drug Administration for the treatment of hormone receptor-positive metastatic breast cancer with PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α) mutation. In recent years a number of adverse effects have been observed to be associated with this therapy, the most notable of which is hyperglycemia. A literature search was conducted to include case studies, case series, systematic reviews, and meta-analyses within the last 10 years that evaluated patients with PIK3CA-mutated hormone receptor-positive, human epidermal growth factor receptor 2 negative metastatic breast cancer. Hyperglycemia was a notable adverse effect that was found in the majority of patients without preexisting diabetes mellitus. Patients with hyperglycemia were in the high-risk groups of advanced age, prediabetes mellitus or history of insulin resistance, increased body mass index, increased blood monocyte count, and increased hemoglobin A1c (glycated hemoglobin). Hyperglycemia was manageable with antihyperglycemic agents and dose modification/discontinuation of alpelisib with no severe progression. Other notable adverse effects were rash, stomatitis, diarrhea, pneumonitis, reduced appetite, elevated liver enzymes, nausea, fatigue, and rare reports of diabetic ketoacidosis. This literature review aims to highlight the incidence and risk factors of alpelisib-induced hyperglycemia in greater depth.
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Affiliation(s)
- Anika Annoor
- From Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas
| | | | | | | | - Arowa Yasmeen
- the Department of Computer Science, University of Dallas, Dallas, Texas
| | - Parisa Tarannum
- the GPST1 East Kent Hospitals University NHS Foundation Trust, East Kent, UK
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Tokat ÜM, Bilgiç ŞN, Aydın E, Adibi A, Özgü E, Tutar O, Demiray M. Elacestrant plus alpelisib in an ESR1 and PIK3CA co-mutated and heavily pretreated metastatic breast cancer: the first case report for combination efficacy and safety. Ther Adv Med Oncol 2024; 16:17588359241297101. [PMID: 39539943 PMCID: PMC11558728 DOI: 10.1177/17588359241297101] [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: 08/05/2024] [Accepted: 10/17/2024] [Indexed: 11/16/2024] Open
Abstract
Breast cancer (BC) is the leading cause of cancer-related mortality among women, and hormone receptor (HR)-positive subtype makes up the majority of all cases. The standard of care in HR+/HER2- metastatic BC (MBC) is endocrine therapy (ET) plus a CDK4/6 inhibitor (CDK4/6i). ESR1 mutations could impair the clinical efficacy of the ETs. Similarly, PIK3CA mutations may serve as a negative prognostic marker. Furthermore, MBC is challenging to treat despite new drug approvals. Our patient received multiple lines of ET ± CDK4/6i and chemotherapy but persistently progressed after each or stopped the treatment due to adverse events. Here we showed for the first time that an all-oral combination of elacestrant plus alpelisib was feasible, tolerable, and clinically active in an ESR1 and PIK3CA co-mutated and heavily pretreated patient. We achieved a remarkable response in the metastatic lesions with minor toxicity issues. This case highlights the importance of utilizing up-to-date therapeutic agents and reactive decision-making during personalized cancer treatment.
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Affiliation(s)
- Ünal Metin Tokat
- Precision Oncology Center, Medicana Health Group, Istanbul, Türkiye
| | | | - Esranur Aydın
- Precision Oncology Center, Medicana Health Group, Istanbul, Türkiye
| | - Ashkan Adibi
- Precision Oncology Center, Medicana Health Group, Istanbul, Türkiye
- Division of Cancer Genetics, Department of Basic Oncology, Institute of Oncology, Istanbul University, Istanbul, Türkiye
| | - Eylül Özgü
- Precision Oncology Center, Medicana Health Group, Istanbul, Türkiye
| | - Onur Tutar
- Department of Internal Medicine, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Türkiye
| | - Mutlu Demiray
- Precision Oncology Center, Medicana Health Group, Istanbul, Türkiye
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Rubovszky G. The role of everolimus in metastatic breast cancer and possibilities of moving forward-a narrative review. ANNALS OF TRANSLATIONAL MEDICINE 2024; 12:68. [PMID: 39118946 PMCID: PMC11304436 DOI: 10.21037/atm-23-1583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 09/17/2023] [Indexed: 08/10/2024]
Abstract
Background and Objective In hormone-receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer endocrine-based therapies are preferred over chemotherapy. One of the treatment options is the combination of everolimus with exemestane or other endocrine drug in later lines mainly based on progression-free survival (PFS) results of the phase 3 BOLERO-2 trial. Altogether, clinical trials did not prove an overall survival (OS) benefit and considerable side effects hampered its application in the day-by-day practice. In recent years CDK4/6-inhibitors became a first-choice combination partner to the endocrine treatment, everolimus still has a place within the treatment armamentarium. Although everolimus is a targeted drug, there is no accepted predictive biomarker and further patient selection is not possible. However, several directions can be defined how to optimally use everolimus. For update information on everolimus treatment in breast cancer I have performed a literature search. Methods I used the keywords "breast cancer" and "everolimus" and extended the search in PubMed from 01/01/2014 to 10/02/2023. I considered all phase 3 trials, the phase 1-2 trials with not repetitive information, studies with biomarker results and I also checked review articles to identify potential relevant other clinical trial reports. I also have made a search in clinicaltrials.gov for recently completed and ongoing trials. Key Content and Findings I summarized the search results in this concise and brief report focusing on main trial results and ongoing research with everolimus. Conclusions The most promising research directions seem to be further investigations for useable predictive biomarkers, for combinations with other targeted drugs (even in a triple combination) and for the feasibility of pharmacologically guided dosing method.
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Affiliation(s)
- Gabor Rubovszky
- Department of Thoracic and Abdominal Tumors and Clinical Pharmacology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary
- Department of Oncology, Semmelweis University, Budapest, Hungary
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Cui Y, Ran R, Da Y, Zhang H, Jiang M, Qi X, Zhang W, Niu L, Zhou Y, Zhou C, Tang X, Wang K, Yan Y, Ren Y, Dong D, Zhou Y, Wang H, Gong J, Hu F, Zhao S, Zhang H, Zhang C, Yang J. The combination of breast cancer PDO and mini-PDX platform for drug screening and individualized treatment. J Cell Mol Med 2024; 28:e18374. [PMID: 38722288 PMCID: PMC11081008 DOI: 10.1111/jcmm.18374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 03/05/2024] [Accepted: 04/16/2024] [Indexed: 05/12/2024] Open
Abstract
The majority of advanced breast cancers exhibit strong aggressiveness, heterogeneity, and drug resistance, and currently, the lack of effective treatment strategies is one of the main challenges that cancer research must face. Therefore, developing a feasible preclinical model to explore tailored treatments for refractory breast cancer is urgently needed. We established organoid biobanks from 17 patients with breast cancer and characterized them by immunohistochemistry (IHC) and next generation sequencing (NGS). In addition, we in the first combination of patient-derived organoids (PDOs) with mini-patient-derived xenografts (Mini-PDXs) for the rapid and precise screening of drug sensitivity. We confirmed that breast cancer organoids are a high-fidelity three-dimension (3D) model in vitro that recapitulates the original tumour's histological and genetic features. In addition, for a heavily pretreated patient with advanced drug-resistant breast cancer, we combined PDO and Mini-PDX models to identify potentially effective combinations of therapeutic agents for this patient who were alpelisib + fulvestrant. In the drug sensitivity experiment of organoids, we observed changes in the PI3K/AKT/mTOR signalling axis and oestrogen receptor (ER) protein expression levels, which further verified the reliability of the screening results. Our study demonstrates that the PDO combined with mini-PDX model offers a rapid and precise drug screening platform that holds promise for personalized medicine, improving patient outcomes and addressing the urgent need for effective therapies in advanced breast cancer.
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Affiliation(s)
- Yuxin Cui
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Ran Ran
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Yanyan Da
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Center for Molecular Diagnosis and Precision MedicineThe First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
| | - Huiwen Zhang
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Meng Jiang
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Xin Qi
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Wei Zhang
- Department of Breast SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Ligang Niu
- Department of Breast SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Yuhui Zhou
- Department of Breast SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Can Zhou
- Department of Breast SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Xiaojiang Tang
- Department of Breast SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Ke Wang
- Department of Breast SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Yu Yan
- Department of Breast SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Yu Ren
- Department of Breast SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Danfeng Dong
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Yan Zhou
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Hui Wang
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Jin Gong
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Fang Hu
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Shidi Zhao
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Huimin Zhang
- Department of Breast SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
| | - Chengsheng Zhang
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Center for Molecular Diagnosis and Precision MedicineThe First Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityNanchangJiangxiChina
| | - Jin Yang
- Precision Medicine Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Cancer Center, The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiPeople's Republic of China
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11
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Nicolini A, Ferrari P. Targeted Therapies and Drug Resistance in Advanced Breast Cancer, Alternative Strategies and the Way beyond. Cancers (Basel) 2024; 16:466. [PMID: 38275906 PMCID: PMC10814066 DOI: 10.3390/cancers16020466] [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: 12/08/2023] [Revised: 01/16/2024] [Accepted: 01/19/2024] [Indexed: 01/27/2024] Open
Abstract
"Targeted therapy" or "precision medicine" is a therapeutic strategy launched over two decades ago. It relies on drugs that inhibit key molecular mechanisms/pathways or genetic/epigenetic alterations that promote different cancer hallmarks. Many clinical trials, sponsored by multinational drug companies, have been carried out. During this time, research has increasingly uncovered the complexity of advanced breast cancer disease. Despite high expectations, patients have seen limited benefits from these clinical trials. Commonly, only a minority of trials are successful, and the few approved drugs are costly. The spread of this expensive therapeutic strategy has constrained the resources available for alternative research. Meanwhile, due to the high cost/benefit ratio, other therapeutic strategies have been proposed by researchers over time, though they are often not pursued due to a focus on precision medicine. Notable among these are drug repurposing and counteracting micrometastatic disease. The former provides an obvious answer to expensive targeted therapies, while the latter represents a new field to which efforts have recently been devoted, offering a "way beyond" the current research.
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Affiliation(s)
- Andrea Nicolini
- Department of Oncology, Transplantations and New Technologies in Medicine, University of Pisa, 56126 Pisa, Italy
| | - Paola Ferrari
- Unit of Oncology, Department of Medical and Oncological Area, Azienda Ospedaliera—Universitaria Pisana, 56125 Pisa, Italy;
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12
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Tang B, Ma W, Lin Y. Emerging applications of anti-angiogenic nanomaterials in oncotherapy. J Control Release 2023; 364:61-78. [PMID: 37871753 DOI: 10.1016/j.jconrel.2023.10.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 10/08/2023] [Accepted: 10/16/2023] [Indexed: 10/25/2023]
Abstract
Angiogenesis is the process of generating new blood vessels from pre-existing vasculature. Under normal conditions, this process is delicately controlled by pro-angiogenic and anti-angiogenic factors. Tumor cells can produce plentiful pro-angiogenic molecules promoting pathological angiogenesis for uncontrollable growth. Therefore, anti-angiogenic therapy, which aims to inhibit tumor angiogenesis, has become an attractive approach for oncotherapy. However, classic anti-angiogenic agents have several limitations in clinical use, such as lack of specific targeting, low bioavailability, and poor therapeutic outcomes. Hence, alternative angiogenic inhibitors are highly desired. With the emergence of nanotechnology, various nanomaterials have been designed for anti-angiogenesis purposes, offering promising features like excellent targeting capabilities, reduced side effects, and enhanced therapeutic efficacy. In this review, we describe tumor vascular features, discuss current dilemma of traditional anti-angiogenic medicines in oncotherapy, and underline the potential of nanomaterials in tumor anti-angiogenic therapy. Moreover, we discuss the current challenges of anti-angiogenic cancer treatment. We expect that this summary of anti-angiogenic nanomaterials in oncotherapy will offer valuable insights, facilitating their extensive applications in the future.
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Affiliation(s)
- Bicai Tang
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; Sichuan Provincial Engineering Research Center of Oral Biomaterials, Chengdu, Sichuan 610041, China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China
| | - Wenjuan Ma
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; Sichuan Provincial Engineering Research Center of Oral Biomaterials, Chengdu, Sichuan 610041, China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China.
| | - Yunfeng Lin
- State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China; Sichuan Provincial Engineering Research Center of Oral Biomaterials, Chengdu, Sichuan 610041, China; Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, PR China.
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13
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Lawson M, Cureton N, Ros S, Cheraghchi-Bashi A, Urosevic J, D'Arcy S, Delpuech O, DuPont M, Fisher DI, Gangl ET, Lewis H, Trueman D, Wali N, Williamson SC, Moss J, Montaudon E, Derrien H, Marangoni E, Miragaia RJ, Gagrica S, Morentin-Gutierrez P, Moss TA, Maglennon G, Sutton D, Polanski R, Rosen A, Cairns J, Zhang P, Sánchez-Guixé M, Serra V, Critchlow SE, Scott JS, Lindemann JP, Barry ST, Klinowska T, Morrow CJ, S Carnevalli L. The Next-Generation Oral Selective Estrogen Receptor Degrader Camizestrant (AZD9833) Suppresses ER+ Breast Cancer Growth and Overcomes Endocrine and CDK4/6 Inhibitor Resistance. Cancer Res 2023; 83:3989-4004. [PMID: 37725704 PMCID: PMC10690091 DOI: 10.1158/0008-5472.can-23-0694] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 07/11/2023] [Accepted: 09/15/2023] [Indexed: 09/21/2023]
Abstract
Oral selective estrogen receptor degraders (SERD) could become the backbone of endocrine therapy (ET) for estrogen receptor-positive (ER+) breast cancer, as they achieve greater inhibition of ER-driven cancers than current ETs and overcome key resistance mechanisms. In this study, we evaluated the preclinical pharmacology and efficacy of the next-generation oral SERD camizestrant (AZD9833) and assessed ER-co-targeting strategies by combining camizestrant with CDK4/6 inhibitors (CDK4/6i) and PI3K/AKT/mTOR-targeted therapy in models of progression on CDK4/6i and/or ET. Camizestrant demonstrated robust and selective ER degradation, modulated ER-regulated gene expression, and induced complete ER antagonism and significant antiproliferation activity in ESR1 wild-type (ESR1wt) and mutant (ESR1m) breast cancer cell lines and patient-derived xenograft (PDX) models. Camizestrant also delivered strong antitumor activity in fulvestrant-resistant ESR1wt and ESR1m PDX models. Evaluation of camizestrant in combination with CDK4/6i (palbociclib or abemaciclib) in CDK4/6-naive and -resistant models, as well as in combination with PI3Kαi (alpelisib), mTORi (everolimus), or AKTi (capivasertib), indicated that camizestrant was active with CDK4/6i or PI3K/AKT/mTORi and that antitumor activity was further increased by the triple combination. The response was observed independently of PI3K pathway mutation status. Overall, camizestrant shows strong and broad antitumor activity in ER+ breast cancer as a monotherapy and when combined with CDK4/6i and PI3K/AKT/mTORi. SIGNIFICANCE Camizestrant, a next-generation oral SERD, shows promise in preclinical models of ER+ breast cancer alone and in combination with CDK4/6 and PI3K/AKT/mTOR inhibitors to address endocrine resistance, a current barrier to treatment.
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Affiliation(s)
- Mandy Lawson
- The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom
| | - Natalie Cureton
- The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom
| | - Susana Ros
- The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom
| | | | - Jelena Urosevic
- The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom
| | - Sophie D'Arcy
- The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom
| | - Oona Delpuech
- The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom
| | - Michelle DuPont
- Research and Early Development, Oncology R&D, AstraZeneca, Waltham, Massachusetts
| | - David I. Fisher
- Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
| | - Eric T. Gangl
- Research and Early Development, Oncology R&D, AstraZeneca, Waltham, Massachusetts
| | - Hilary Lewis
- The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom
| | - Dawn Trueman
- The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom
| | - Neha Wali
- The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom
| | | | - Jennifer Moss
- The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom
| | | | | | | | | | - Sladjana Gagrica
- The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom
| | | | - Thomas A. Moss
- The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom
| | - Gareth Maglennon
- Clinical Pharmacology and Safety Sciences, Biopharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
| | - Daniel Sutton
- The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom
| | - Radoslaw Polanski
- Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
| | - Alan Rosen
- Research and Early Development, Oncology R&D, AstraZeneca, Waltham, Massachusetts
| | - Jonathan Cairns
- Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
| | - Pei Zhang
- The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom
| | - Mònica Sánchez-Guixé
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Violeta Serra
- Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Susan E. Critchlow
- The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom
| | - James S. Scott
- The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom
| | | | - Simon T. Barry
- The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom
| | - Teresa Klinowska
- Late Development, Oncology R&D, AstraZeneca, Cambridge, United Kingdom
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14
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Yang J, Friedman R. Combination strategies to overcome drug resistance in FLT + acute myeloid leukaemia. Cancer Cell Int 2023; 23:161. [PMID: 37568211 PMCID: PMC10416533 DOI: 10.1186/s12935-023-03000-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 07/25/2023] [Indexed: 08/13/2023] Open
Abstract
BACKGROUND Acute myeloid leukaemia (AML) remains difficult to treat despite the development of novel formulations and targeted therapies. Activating mutations in the FLT3 gene are common among patients and make the tumour susceptible to FLT3 inhibitors, but resistance to such inhibitors develops quickly. METHODS We examined combination therapies aimed at FLT3+-AML, and studied the development of resistance using a newly developed protocol. Combinations of FLT3, CDK4/6 and PI3K inhibitors were tested for synergism. RESULTS We show that AML cells express CDK4 and that the CDK4/6 inhibitors palbociclib and abemaciclib inhibit cellular growth. PI3K inhibitors were also effective in inhibiting the growth of AML cell lines that express FLT3-ITD. Whereas resistance to quizartinib develops quickly, the combinations overcome such resistance. CONCLUSIONS This study suggests that a multi-targeted intervention involving a CDK4/6 inhibitor with a FLT3 inhibitor or a pan-PI3K inhibitor might be a valuable therapeutic strategy for AML to overcome drug resistance. Moreover, many patients cannot tolerate high doses of the drugs that were studied (quizartinib, palbociclib and PI3K inhibitors) for longer periods, and it is therefore of high significance that the drugs act synergistically and lower doses can be used.
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Affiliation(s)
- Jingmei Yang
- Department of Chemistry and Biomedical Science, Linnaeus University, Kalmar Campus, 391 82, Kalmar, Sweden
| | - Ran Friedman
- Department of Chemistry and Biomedical Science, Linnaeus University, Kalmar Campus, 391 82, Kalmar, Sweden.
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15
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Bertino FJ, Hawkins CM. Contemporary management of extracranial vascular malformations. Pediatr Radiol 2023; 53:1600-1617. [PMID: 37156889 DOI: 10.1007/s00247-023-05670-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 04/08/2023] [Accepted: 04/10/2023] [Indexed: 05/10/2023]
Abstract
Vascular malformations are congenital vascular anomalies that originate because of disorganized angiogenesis, most commonly from spontaneous somatic genetic mutations. The modern management of vascular malformations requires a multidisciplinary team that offers patients the gamut of medical, surgical, and percutaneous treatment options with supportive care. This manuscript discusses the standard and contemporary management strategies surrounding extracranial vascular malformations and overgrowth syndromes.
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Affiliation(s)
- Frederic J Bertino
- Department of Radiology, Interventional Radiology Section, NYU Langone Health/NYU Grossman School of Medicine, 2nd Floor Radiology-Tisch Hospital, 550 First Avenue, New York, NY, 10016, USA.
| | - C Matthew Hawkins
- Department of Radiology, Division of Interventional Radiology, Children's Healthcare of Atlanta, Atlanta, GA, USA
- Department of Radiology and Imaging Sciences, Division of Interventional Radiology and Image Guided Medicine, Emory University School of Medicine, Atlanta, GA, USA
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16
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Lathigara D, Kaushal D, Wilson RB. Molecular Mechanisms of Western Diet-Induced Obesity and Obesity-Related Carcinogenesis-A Narrative Review. Metabolites 2023; 13:metabo13050675. [PMID: 37233716 DOI: 10.3390/metabo13050675] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 05/05/2023] [Accepted: 05/18/2023] [Indexed: 05/27/2023] Open
Abstract
The present study aims to provide a narrative review of the molecular mechanisms of Western diet-induced obesity and obesity-related carcinogenesis. A literature search of the Cochrane Library, Embase and Pubmed databases, Google Scholar and the grey literature was conducted. Most of the molecular mechanisms that induce obesity are also involved in the twelve Hallmarks of Cancer, with the fundamental process being the consumption of a highly processed, energy-dense diet and the deposition of fat in white adipose tissue and the liver. The generation of crown-like structures, with macrophages surrounding senescent or necrotic adipocytes or hepatocytes, leads to a perpetual state of chronic inflammation, oxidative stress, hyperinsulinaemia, aromatase activity, activation of oncogenic pathways and loss of normal homeostasis. Metabolic reprogramming, epithelial mesenchymal transition, HIF-1α signalling, angiogenesis and loss of normal host immune-surveillance are particularly important. Obesity-associated carcinogenesis is closely related to metabolic syndrome, hypoxia, visceral adipose tissue dysfunction, oestrogen synthesis and detrimental cytokine, adipokine and exosomal miRNA release. This is particularly important in the pathogenesis of oestrogen-sensitive cancers, including breast, endometrial, ovarian and thyroid cancer, but also 'non-hormonal' obesity-associated cancers such as cardio-oesophageal, colorectal, renal, pancreatic, gallbladder and hepatocellular adenocarcinoma. Effective weight loss interventions may improve the future incidence of overall and obesity-associated cancer.
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Affiliation(s)
- Dhruvi Lathigara
- Department General Surgery, UWS, Campbelltown Hospital, Campbelltown, NSW 2560, Australia
| | - Devesh Kaushal
- Department General Surgery, UWS, Campbelltown Hospital, Campbelltown, NSW 2560, Australia
| | - Robert Beaumont Wilson
- Department Upper Gastrointestinal Surgery, UNSW, Liverpool Hospital, Liverpool, NSW 2170, Australia
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17
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Ye Y, Huang Z, Zhang M, Li J, Zhang Y, Lou C. Synergistic therapeutic potential of alpelisib in cancers (excluding breast cancer): Preclinical and clinical evidences. Biomed Pharmacother 2023; 159:114183. [PMID: 36641927 DOI: 10.1016/j.biopha.2022.114183] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/19/2022] [Accepted: 12/28/2022] [Indexed: 01/15/2023] Open
Abstract
The phosphoinositide 3-kinase (PI3K) signaling pathway is well-known for its important role in cancer growth, proliferation and migration. The activation of PI3K pathway is always connected with endocrine resistance and poor prognosis in cancers. Alpelisib, a selective inhibitor of PI3K, has been demonstrated to be effective in combination with endocrine therapy in HR+ PIK3CA-mutated advanced breast cancer in preclinical and clinical trials. Recently, the synergistic effects of alpelisib combined with targeted agents have been widely reported in PIK3CA-mutated cancer cells, such as breast, head and neck squamous cell carcinoma (HNSCC), cervical, liver, pancreatic and lung cancer. However, previous reviews mainly focused on the pharmacological activities of alpelisib in breast cancer. The synergistic therapeutic potential of alpelisib in other cancers has not yet been well reviewed. In this review, an extensive study of related literatures (published until December 20, 2022) regarding the anti-cancer functions and synergistic effects of alpelisib was carried out through the databases. Useful information was extracted. We summarized the preclinical and clinical studies of alpelisib in combination with targeted anti-cancer agents in cancer treatment (excluding breast cancer). The combinations of alpelisib and other targeted agents significantly improved the therapeutic efficacy both in preclinical and clinical studies. Unfortunately, synergistic therapies still could not effectively avoid the possible toxicities and adverse events during treatment. Finally, some prospects for the combination studies in cancer treatment were provided in the paper. Taken together, this review provided valuable information for alpelisib in preclinical and clinical applications.
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Affiliation(s)
- Yuhao Ye
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Zhiyu Huang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Maoqing Zhang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Jiayue Li
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Yiqiong Zhang
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| | - Chenghua Lou
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
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18
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Cheng QW, Shen HL, Dong ZH, Zhang QQ, Wang YF, Yan J, Wang YS, Zhang NG. Pneumocystis jirovecii diagnosed by next-generation sequencing of bronchoscopic alveolar lavage fluid: A case report and review of literature. World J Clin Cases 2023; 11:866-873. [PMID: 36818625 PMCID: PMC9928697 DOI: 10.12998/wjcc.v11.i4.866] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/22/2022] [Accepted: 01/09/2023] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND The advent of molecular targeted agents and immune checkpoint inhibitors has greatly improved the treatment of advanced renal cell carcinoma (RCC), thus significantly improving patient survival. The incidence of rare drug-related adverse events has gained increased attention. CASE SUMMARY We report a patient with advanced RCC treated with multiple lines of molecular targeted agents and immune checkpoint inhibitors, who developed a pulmonary infection after treatment with everolimus in combination with lenvatinib. Determining the pathogenic organism was difficult, but it was eventually identified as Pneumocystis jirovecii by next-generation sequencing (NGS) of bronchoscopic alveolar lavage fluid (BALF) and successfully treated with trimethoprim-sulfamethoxazole. CONCLUSION Rare pulmonary infections caused by molecular targeted agents are not uncommon in clinical practice, but their diagnosis is difficult. Evaluating BALF with NGS is a good method for rapid diagnosis of such infections.
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Affiliation(s)
- Qing-Wei Cheng
- Department of Oncology, The Sixth Division Hospital, Xinjiang Production and Construction Corps, Wujiaqu 831300, Xinjiang Uygur Autonomous Regions, China
| | - Hong-Li Shen
- Department of Oncology, The Sixth Division Hospital, Xinjiang Production and Construction Corps, Wujiaqu 831300, Xinjiang Uygur Autonomous Regions, China
| | - Zhi-Hui Dong
- Department of Oncology, The Sixth Division Hospital, Xinjiang Production and Construction Corps, Wujiaqu 831300, Xinjiang Uygur Autonomous Regions, China
| | - Qian-Qian Zhang
- Department of Oncology, The Sixth Division Hospital, Xinjiang Production and Construction Corps, Wujiaqu 831300, Xinjiang Uygur Autonomous Regions, China
| | - Ya-Fen Wang
- Department of Oncology, The Sixth Division Hospital, Xinjiang Production and Construction Corps, Wujiaqu 831300, Xinjiang Uygur Autonomous Regions, China
| | - Jin Yan
- Department of Oncology, The Sixth Division Hospital, Xinjiang Production and Construction Corps, Wujiaqu 831300, Xinjiang Uygur Autonomous Regions, China
| | - Yu-Sheng Wang
- Department of Gastrointestinal Oncology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan 030013, Shanxi Province, China
| | - Ning-Gang Zhang
- Department of Gastrointestinal Oncology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan 030013, Shanxi Province, China
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19
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Hsu H, Chu P, Chang T, Huang K, Hung W, Jiang SS, Lin H, Tsai H. Mitochondrial phosphoenolpyruvate carboxykinase promotes tumor growth in estrogen receptor-positive breast cancer via regulation of the mTOR pathway. Cancer Med 2022; 12:1588-1601. [PMID: 35757841 PMCID: PMC9883444 DOI: 10.1002/cam4.4969] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 06/03/2022] [Accepted: 06/11/2022] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Tumor cells may aberrantly express metabolic enzymes to adapt to their environment for survival and growth. Targeting cancer-specific metabolic enzymes is a potential therapeutic strategy. Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the conversion of oxaloacetate to phosphoenolpyruvate and links the tricarboxylic acid cycle and glycolysis/gluconeogenesis. Mitochondrial PEPCK (PEPCK-M), encoded by PCK2, is an isozyme of PEPCK and is distributed in mitochondria. Overexpression of PCK2 has been identified in many human cancers and demonstrated to be important for the survival program initiated upon metabolic stress in cancer cells. We evaluated the expression status of PEPCK-M and investigated the function of PEPCK-M in breast cancer. METHODS We checked the expression status of PEPCK-M in breast cancer samples by immunohistochemical staining. We knocked down or overexpressed PCK2 in breast cancer cell lines to investigate the function of PEPCK-M in breast cancer. RESULTS PEPCK-M was highly expressed in estrogen receptor-positive (ER+ ) breast cancers. Decreased cell proliferation and G0 /G1 arrest were induced in ER+ breast cancer cell lines by knockdown of PCK2. PEPCK-M promoted the activation of mTORC1 downstream signaling molecules and the E2F1 pathways in ER+ breast cancer. In addition, glucose uptake, intracellular glutamine levels, and mTORC1 pathways activation by glucose and glutamine in ER+ breast cancer were attenuated by PCK2 knockdown. CONCLUSION PEPCK-M promotes proliferation and cell cycle progression in ER+ breast cancer via upregulation of the mTORC1 and E2F1 pathways. PCK2 also regulates nutrient status-dependent mTORC1 pathway activation in ER+ breast cancer. Further studies are warranted to understand whether PEPCK-M is a potential therapeutic target for ER+ breast cancer.
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Affiliation(s)
- Hui‐Ping Hsu
- Department of SurgeryNational Cheng Kung University Hospital, College of Medicine, National Cheng Kung UniversityTainanTaiwan
| | - Pei‐Yi Chu
- Department of PathologyShow Chwan Memorial HospitalChanghuaTaiwan,National Institute of Cancer ResearchNational Health Research InstitutesTainanTaiwan,School of Medicine, College of MedicineFu Jen Catholic UniversityNew Taipei CityTaiwan,Department of Post‐Baccalaureate Medicine, College of MedicineNational Chung Hsing UniversityTaichungTaiwan
| | - Tsung‐Ming Chang
- National Institute of Cancer ResearchNational Health Research InstitutesTainanTaiwan,Department of Medical Laboratory ScienceCollege of Medical Science and Technology, I‐Shou UniversityKaohsiungTaiwan
| | - Kuo‐Wei Huang
- National Institute of Cancer ResearchNational Health Research InstitutesTainanTaiwan
| | - Wen‐Chun Hung
- National Institute of Cancer ResearchNational Health Research InstitutesTainanTaiwan
| | - Shih Sheng Jiang
- National Institute of Cancer ResearchNational Health Research InstitutesTainanTaiwan
| | - Hui‐You Lin
- National Institute of Cancer ResearchNational Health Research InstitutesTainanTaiwan
| | - Hui‐Jen Tsai
- National Institute of Cancer ResearchNational Health Research InstitutesTainanTaiwan,Department of Oncology, National Cheng Kung University Hospital, College of MedicineNational Cheng Kung UniversityTainanTaiwan,Department of Internal Medicine, Kaohsiung Medical University HospitalKaohsiung Medical UniversityKaohsiungTaiwan
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20
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Zuo Q, Park NH, Lee JK, Madak Erdogan Z. Liver Metastatic Breast Cancer: Epidemiology, Dietary Interventions, and Related Metabolism. Nutrients 2022; 14:2376. [PMID: 35745105 PMCID: PMC9228756 DOI: 10.3390/nu14122376] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 05/22/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
The median overall survival of patients with metastatic breast cancer is only 2-3 years, and for patients with untreated liver metastasis, it is as short as 4-8 months. Improving the survival of women with breast cancer requires more effective anti-cancer strategies, especially for metastatic disease. Nutrients can influence tumor microenvironments, and cancer metabolism can be manipulated via a dietary modification to enhance anti-cancer strategies. Yet, there are no standard evidence-based recommendations for diet therapies before or during cancer treatment, and few studies provide definitive data that certain diets can mediate tumor progression or therapeutic effectiveness in human cancer. This review focuses on metastatic breast cancer, in particular liver metastatic forms, and recent studies on the impact of diets on disease progression and treatment.
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Affiliation(s)
- Qianying Zuo
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; (Q.Z.); (N.H.P.)
| | - Nicole Hwajin Park
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; (Q.Z.); (N.H.P.)
| | - Jenna Kathryn Lee
- Department of Neuroscience, Northwestern University, Evanston, IL 60208, USA;
| | - Zeynep Madak Erdogan
- Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; (Q.Z.); (N.H.P.)
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Carl R. Woese Institute of Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Department of Biomedical and Translational Sciences, Carle-Illinois College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
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21
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Campone M, Bachelot T, Treilleux I, Pistilli B, Salleron J, Seegers V, Arnedos M, Loussouarn D, Wang Q, Vanlemmens L, Jimenez M, Rios M, Diéras V, Leroux A, Paintaud G, Rezai K, André F, Lion M, Merlin JL. A phase II randomised study of preoperative trastuzumab alone or combined with everolimus in patients with early HER2-positive breast cancer and predictive biomarkers (RADHER trial). Eur J Cancer 2021; 158:169-180. [PMID: 34678678 DOI: 10.1016/j.ejca.2021.09.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 09/06/2021] [Accepted: 09/11/2021] [Indexed: 11/28/2022]
Abstract
INTRODUCTION Resistance to trastuzumab in breast cancer is an ongoing challenge. Clinical and biological effects of co-targeting HER2 and mammalian target of rapamycin (mTOR) in patients with HER2-positive early operable breast cancer via the addition of everolimus to preoperative trastuzumab were evaluated in a phase II randomised study. METHODS Patients were randomised 1:1 to receive trastuzumab (4 mg/kg initial dose then 2 mg/kg weekly for 5 weeks) alone or combined with everolimus (10 mg/day for 6 weeks) and then underwent surgery. Tumours were assessed by clinical examination and echography at the baseline and on treatment. The primary end-point was the clinical response rate at 6 weeks. Pathological response and safety were also evaluated. Baseline and surgery tumour samples were assessed by immunohistochemistry and multiplex immunoanalysis for predictive downstream effectors of the PI3K/AKT/mTOR and MAP kinase (MAPK) pathways. RESULTS Eighty-two patients were enrolled, 41 per arm. The clinical response rates were 34.1% and 43.9% with trastuzumab alone and combined with everolimus, respectively. Pathological response rates were 43.6% and 47.5%, respectively. Addition of everolimus increased toxicity, notably mucositis (82.5% versus 5.0%) and rash (57.5% versus 10.0%), but grade III/IV events were rare. No correlation between response to treatments and baseline candidate biomarkers was identified, except for PIK3CA mutations which were found to predict trastuzumab resistance. Significant changes were seen in several MAPK pathway effectors after combination therapy. CONCLUSIONS The addition of everolimus did not improve the efficacy, but induced MAPK signalling. Combination therapy to overcome pathway cross-talk should be considered to maximise the effectiveness of trastuzumab in this setting. ClinicalTrial.gov Identifier NCT00674414.
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Affiliation(s)
- Mario Campone
- Department of Medical Oncology/ Cancer Research Center UMR-INSERM U892/CNRS 6299/ Bioinformatics Unit, Institut de Cancérologie de L'Ouest, Nantes, France
| | - Thomas Bachelot
- Department of Medical Oncology, Centre Léon Bérard, INSERM U1052, Lyon, France
| | - Isabelle Treilleux
- Department of Pathology and Biopathology, Centre Léon Bérard, Lyon, France
| | | | - Julia Salleron
- Methodology and Biostatistics Unit, Institut de Cancérologie de Lorraine, Vandoeuvre-Les-Nancy, France
| | - Valérie Seegers
- Oncology Data Factory and Analytics, Institut de Cancérologie de L'Ouest, Nantes, France
| | - Monica Arnedos
- Department of Medicine, Gustave Roussy, Villejuif, France
| | | | - Qing Wang
- Genomic Platform-Cancer Research Center of Lyon, Centre Léon Bérard, Lyon, France
| | | | | | - Maria Rios
- Department of Medical Oncology, Institut de Cancérologie de Lorraine, Vandoeuvre-les-Nancy, France
| | | | - Agnès Leroux
- Department of Biopathology, Institut de Cancérologie de Lorraine, Université de Lorraine, CNRS UMR 7039, CRAN, Vandoeuvre-Les-Nancy, France
| | - Gilles Paintaud
- François Rabelais University, CNRS, UMR 7292, Genetics, Immunotherapy, Chemistry and Cancer, Tours, France
| | - Keyvan Rezai
- Radio-Pharmacology Department, Institut Curie-Hôpital Rene Huguenin, Saint-Cloud, France
| | - Fabrice André
- Department of Medicine, Gustave Roussy, Villejuif, France
| | - Maëva Lion
- Department of Biopathology, Institut de Cancérologie de Lorraine, Université de Lorraine, CNRS UMR 7039, CRAN, Vandoeuvre-Les-Nancy, France
| | - Jean-Louis Merlin
- Department of Biopathology, Institut de Cancérologie de Lorraine, Université de Lorraine, CNRS UMR 7039, CRAN, Vandoeuvre-Les-Nancy, France.
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22
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Zeng J, He SL, Li LJ, Wang C. Hsp90 up-regulates PD-L1 to promote HPV-positive cervical cancer via HER2/PI3K/AKT pathway. Mol Med 2021; 27:130. [PMID: 34666670 PMCID: PMC8524852 DOI: 10.1186/s10020-021-00384-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 09/20/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND HPV16 is the predominant cancer-causing strain that is responsible for over 50% of all cervical cancers. In this study, we aim to investigate the therapeutic effect of heat shock protein 90 (Hsp90) knockdown on HPV16+ cervical cancer progression and the underlying mechanism. METHODS The transcript and protein expression of Hsp90 in normal cervical and HPV16+ cervical cancer tissues and cell lines were detected by qRT-PCR, immunohistochemistry staining and Western blot. Hsp90 knockdown clones were established using HPV16+ cervical cancer cell line Caski and SiHa cells. The effect of Hsp90 knockdown on HER2/PI3K/AKT pathway and PD-L1 expression was characterized using qRT-PCR and Western blot analysis. Cell proliferation and migration were determined using MTT and transwell assays. Using mouse xenograft tumor model, the impact of Hsp90 knockdown and PD-L1 overexpression on tumor progression was evaluated. RESULTS Hsp90 expression was up-regulated in HPV16+ cervical cancer tissues and cells. Knockdown of Hsp90 inhibited proliferation and migration of Caski and SiHa cells. PD-L1 expression in cervical cancer tissues was positively correlated with Hsp90 expression, and Hsp90 regulated PD-L1 expression via HER2/PI3K/AKT signaling pathway. The results of mouse xenograft tumor model demonstrated Hsp90 knockdown suppressed tumor formation and overexpression of PD-L1 simultaneously eliminated the cancer-suppressive effect of Hsp90 knockdown. CONCLUSION In this study, we demonstrated a promising tumor-suppressive effect of Hsp90 knockdown in HPV16+ cervical cancers, and investigated the underlying molecular pathway. Our results suggested that Hsp90 knockdown holds great therapeutic potential in treating HPV16+ cervical cancers.
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Affiliation(s)
- Jie Zeng
- Pharmacy Intravenous Admixture Services, The Third Xiangya Hospital of Central South University, Changsha, 410013, Hunan Province, People's Republic of China
| | - Si-Li He
- Department of Gynecology and Obstetrics, The Third Xiangya Hospital of Central South University, No.138, Tongzipo Road, Changsha, 410013, Hunan Province, People's Republic of China
| | - Li-Jie Li
- Department of Gynecology and Obstetrics, The Third Xiangya Hospital of Central South University, No.138, Tongzipo Road, Changsha, 410013, Hunan Province, People's Republic of China
| | - Chen Wang
- Department of Gynecology and Obstetrics, The Third Xiangya Hospital of Central South University, No.138, Tongzipo Road, Changsha, 410013, Hunan Province, People's Republic of China.
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23
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Kaboli PJ, Imani S, Jomhori M, Ling KH. Chemoresistance in breast cancer: PI3K/Akt pathway inhibitors vs the current chemotherapy. Am J Cancer Res 2021; 11:5155-5183. [PMID: 34765318 PMCID: PMC8569340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 06/12/2021] [Indexed: 06/13/2023] Open
Abstract
Breast cancer is the most prevalent type of cancer among women. Several types of drugs, targeting the specific proteins expressed on the breast cancer cell surface (such as receptor tyrosine kinases and immune checkpoint regulators) and proteins involved in cell cycle and motility (including cyclin-dependent kinases, DNA stabilisers, and cytoskeleton modulators) are approved for different subtypes of breast cancer. However, breast cancer also has a poor response to conventional chemotherapy due to intrinsic and acquired resistance, and an Akt fingerprint is detectable in most drug-resistant cases. Overactivation of Akt and its upstream and downstream regulators in resistant breast cancer cells is considered a major potential target for novel anti-cancer therapies, suggesting that Akt signalling acts as a cellular mechanism against chemotherapy. The present review has shown that sustained activation of Akt results in resistance to different types of chemotherapy. Akt signalling plays a cellular defence role against chemotherapy and (1) enhances multi-drug resistance, (2) increases reactive oxygen species at breast tumor microenvironment, (3) enhances anaerobic metabolism, (4) inhibits the tricarboxylic cycle, (5) promotes PD-L1 upregulation, (6) inhibits apoptosis, (7) increases glucose uptake, and more importantly (8) recruits and interconnects the plasma membrane, nucleus, endoplasmic reticulum, and mitochondria to hijack breast cancer cells and rescue these cells from chemotherapy. Therefore, Akt signalling is considered a cellular defence mechanism employed against chemotherapeutic effects. In addition, interfering roles of PI3K/Akt signalling on the current cytotoxic and molecularly targeted therapy as well as immunotherapy of breast cancer are discussed with a clinical approach. Although, alpelisib, a PIK3CA inhibitor, is the only PI3K/Akt pathway inhibitor approved for breast cancer, we also highlight well-evaluated inhibitors of PI3K/Akt signalling based on different subtypes of breast cancer, which are under clinical trials whether as monotherapy or in combination with other types of chemotherapy.
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Affiliation(s)
- Parham Jabbarzadeh Kaboli
- Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical UniversityTaichung 404, Taiwan
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra MalaysiaSerdang, Selangor 43400, Malaysia
| | - Saber Imani
- Department of Oncology, The Affiliated Hospital of Southwest Medical UniversityLuzhou, Sichuan 646000, P. R. China
| | - Masume Jomhori
- Department of Biotechnology Research, Razi Vaccine and Serum Research InstituteMashhad, Iran
| | - King-Hwa Ling
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra MalaysiaSerdang, Selangor 43400, Malaysia
- Department of Genetics, Harvard Medical SchoolBoston, MA 02115, USA
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24
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Hussein S, Khanna P, Yunus N, Gatza ML. Nuclear Receptor-Mediated Metabolic Reprogramming and the Impact on HR+ Breast Cancer. Cancers (Basel) 2021; 13:cancers13194808. [PMID: 34638293 PMCID: PMC8508306 DOI: 10.3390/cancers13194808] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 09/22/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Breast cancer is the most commonly diagnosed and second leading cause of cancer-related deaths in women in the United States, with hormone receptor positive (HR+) tumors representing more than two-thirds of new cases. Recent evidence has indicated that dysregulation of multiple metabolic programs, which can be driven through nuclear receptor activity, is essential for tumor genesis, progression, therapeutic resistance and metastasis. This study will review the current advances in our understanding of the impact and implication of altered metabolic processes driven by nuclear receptors, including hormone-dependent signaling, on HR+ breast cancer. Abstract Metabolic reprogramming enables cancer cells to adapt to the changing microenvironment in order to maintain metabolic energy and to provide the necessary biological macromolecules required for cell growth and tumor progression. While changes in tumor metabolism have been long recognized as a hallmark of cancer, recent advances have begun to delineate the mechanisms that modulate metabolic pathways and the consequence of altered signaling on tumorigenesis. This is particularly evident in hormone receptor positive (HR+) breast cancers which account for approximately 70% of breast cancer cases. Emerging evidence indicates that HR+ breast tumors are dependent on multiple metabolic processes for tumor progression, metastasis, and therapeutic resistance and that changes in metabolic programs are driven, in part, by a number of key nuclear receptors including hormone-dependent signaling. In this review, we discuss the mechanisms and impact of hormone receptor mediated metabolic reprogramming on HR+ breast cancer genesis and progression as well as the therapeutic implications of these metabolic processes in this disease.
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Affiliation(s)
- Shaimaa Hussein
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; (S.H.); (P.K.)
- Department of Radiation Oncology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA
| | - Pooja Khanna
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; (S.H.); (P.K.)
- Department of Radiation Oncology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA
- School of Arts and Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA;
| | - Neha Yunus
- School of Arts and Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA;
| | - Michael L. Gatza
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; (S.H.); (P.K.)
- Department of Radiation Oncology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA
- School of Arts and Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08903, USA;
- Correspondence: ; Tel.: +1-732-235-8751
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25
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Chien TJ. A review of the endocrine resistance in hormone-positive breast cancer. Am J Cancer Res 2021; 11:3813-3831. [PMID: 34522451 PMCID: PMC8414389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 06/25/2021] [Indexed: 06/13/2023] Open
Abstract
Hormone-positive breast cancer (BC) is a unique heterogeneous disease with a favorable prognosis compared to other types of breast cancer. As tumor biology influences the prognosis and clinical treatment, a deep understanding of how the molecular mechanisms regulate hormone sensitivity or resistance is critical in improving the efficacy and overcoming the endocrine resistance. This article comprehensively reviews the endocrine resistance in hormone-positive BC from a molecular and genetic perspective, encompassing the updated treatment and developing direction. This review includes the mechanisms of hormone resistance, which vary from epigenetic changes, crosstalk between signaling networks, cell cycle aberrance, and even change in the tumor microenvironment (TME) or stem cell. These mechanisms may contribute to treatment resistance. Current targeted therapy for hormone-resistant tumors includes PI3K/AKT/mTOR and cdk4/6 inhibitors. Several relevant pathways, biomarkers, and predictor genes have also been identified. Immunotherapy so far has a relatively less crucial role in hormone-positive than in triple-negative BC. Furthermore, the methodology to identify the PDL1 is not standardized. In a molecule and gene study, next-generation sequencing with circulating tumor DNA (ctDNA) has recently appeared as a sensitive and minimally invasive tool worth investigating.
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Affiliation(s)
- Tsai-Ju Chien
- Division of Hemato-Oncology, Department of Internal Medicine, Branch of Zhong-Zhou, Taipei City HospitalTaipei, Taiwan
- Division of Hemato-Oncology, Department of Internal Medicine, Branch of Jen-Ai, Taipei City HospitalTaipei, Taiwan
- Institute of Traditional Medicine, National Yang-Ming Chiao Tung UniversityTaipei, Taiwan
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26
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Molehin D, Filleur S, Pruitt K. Regulation of aromatase expression: Potential therapeutic insight into breast cancer treatment. Mol Cell Endocrinol 2021; 531:111321. [PMID: 33992735 DOI: 10.1016/j.mce.2021.111321] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 04/14/2021] [Accepted: 05/09/2021] [Indexed: 12/13/2022]
Abstract
Estrogen signaling has been implicated in hormone-dependent breast cancer which constitutes >75% of breast cancer diagnosis and other malignancies. Aromatase, the key enzyme involved in the synthesis of estrogen, is often dysregulated in breast cancers. This has led to the administration of aromatase-inhibitors (AIs), commonly used for hormone-dependent breast cancers. Unfortunately, the increasing development of acquired resistance to the current AIs and modulators of estrogen receptors, following initial disease steadiness, has posed a serious clinical challenge in breast cancer treatment. In this review we highlight historical and recent advances on the transcriptional and post-translational regulation of aromatase in both physiological and pathological contexts. We also discuss the different drug combinations targeting various tumor promoting cell signaling pathways currently being developed and tested both in laboratory settings and in the clinic.
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Affiliation(s)
- Deborah Molehin
- Department of Immunology & Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Stephanie Filleur
- Texas Tech University Health Sciences Center, School of Medicine, Lubbock, TX, USA
| | - Kevin Pruitt
- Department of Immunology & Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
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27
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Vernieri C, Nichetti F, Lalli L, Moscetti L, Giorgi CA, Griguolo G, Marra A, Randon G, Rea CG, Ligorio F, Scagnoli S, De Angelis C, Molinelli C, Fabbri A, Ferraro E, Trapani D, Milani A, Agostinetto E, Bernocchi O, Catania G, Vantaggiato A, Palleschi M, Moretti A, Basile D, Cinausero M, Ajazi A, Castagnoli L, Lo Vullo S, Gerratana L, Puglisi F, La Verde N, Arpino G, Rocca A, Ciccarese M, Pedersini R, Fabi A, Generali D, Losurdo A, Montemurro F, Curigliano G, Del Mastro L, Michelotti A, Cortesi E, Guarneri V, Pruneri G, Mariani L, de Braud F. Impact of Baseline and On-Treatment Glycemia on Everolimus-Exemestane Efficacy in Patients with Hormone Receptor-Positive Advanced Breast Cancer (EVERMET). Clin Cancer Res 2021; 27:3443-3455. [PMID: 33785482 DOI: 10.1158/1078-0432.ccr-20-4928] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/24/2021] [Accepted: 03/26/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE The mTOR complex C1 (mTORC1) inhibitor everolimus in combination with the aromatase inhibitor exemestane is an effective treatment for patients with hormone receptor-positive (HR+), HER2-negative (HER2-), advanced breast cancer (HR+/HER2- aBC). However, everolimus can cause hyperglycemia and hyperinsulinemia, which could reactivate the PI3K/protein kinase B (AKT)/mTORC1 pathway and induce tumor resistance to everolimus. EXPERIMENTAL DESIGN We conducted a multicenter, retrospective, Italian study to investigate the impact of baseline and on-treatment (i.e., during first 3 months of therapy) blood glucose levels on progression-free survival (PFS) in patients with HR+/HER2- aBC treated with everolimus-exemestane. RESULTS We evaluated 809 patients with HR+/HER2- aBC treated with everolimus-exemestane as any line of therapy for advanced disease. When evaluated as dichotomous variables, baseline and on-treatment glycemia were not significantly associated with PFS. However, when blood glucose concentration was evaluated as a continuous variable, a multivariable model accounting for clinically relevant patient- and tumor-related variables revealed that both baseline and on-treatment glycemia are associated with PFS, and this association is largely attributable to their interaction. In particular, patients who are normoglycemic at baseline and experience on-treatment diabetes have lower PFS compared with patients who are already hyperglycemic at baseline and experience diabetes during everolimus-exemestane therapy (median PFS, 6.34 vs. 10.32 months; HR, 1.76; 95% confidence interval, 1.15-2.69; P = 0.008). CONCLUSIONS The impact of on-treatment glycemia on the efficacy of everolimus-exemestane therapy in patients with HR+/HER2- aBC depends on baseline glycemia. This study lays the foundations for investigating novel therapeutic approaches to target the glucose/insulin axis in combination with PI3K/AKT/mTORC1 inhibitors in patients with HR+/HER2- aBC.
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Affiliation(s)
- Claudio Vernieri
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. .,IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy
| | - Federico Nichetti
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Luca Lalli
- Unit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Luca Moscetti
- Division of Medical Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | | | - Gaia Griguolo
- Medical Oncology 2, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.,Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy
| | - Antonio Marra
- Division of Early Drug Development for Innovative Therapies, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Giovanni Randon
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Carmen G Rea
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesca Ligorio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Simone Scagnoli
- Department of Medico-Surgical Sciences and Translational Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Claudia De Angelis
- UO Oncologia Medica 2, Ospedale S. Chiara, Dipartimento di Oncologia, Dei Trapianti e Delle Nuove Tecnologie, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
| | - Chiara Molinelli
- IRCCS Ospedale Policlinico San Martino, U.O.S.D. Breast Unit, Genova, Italy
| | - Agnese Fabbri
- Medical Oncology Unit, Belcolle Hospital, Viterbo, Italy
| | - Emanuela Ferraro
- Division of Early Drug Development for Innovative Therapies, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Dario Trapani
- Division of Early Drug Development for Innovative Therapies, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Andrea Milani
- Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy
| | - Elisa Agostinetto
- Medical Oncology and Hematology Unit, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy
| | - Ottavia Bernocchi
- Department of Medical, Surgery and Health Sciences, University of Trieste, Trieste, Italy
| | - Giovanna Catania
- Division of Medical Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | | | - Michela Palleschi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST, Meldola, Italy
| | - Anna Moretti
- Department of Oncology, ASST Fatebenefratelli Sacco - PO Fatebenefratelli, Milan, Italy
| | - Debora Basile
- Department of Medical Oncology, IRCCS Centro di Riferimento Oncologico di Aviano (CRO), Aviano, Italy
| | - Marika Cinausero
- Department of Oncology, ASUFC University Hospital of Udine, Udine, Italy
| | - Arta Ajazi
- IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy
| | - Lorenzo Castagnoli
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Salvatore Lo Vullo
- Unit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Lorenzo Gerratana
- Department of Medical Oncology, IRCCS Centro di Riferimento Oncologico di Aviano (CRO), Aviano, Italy.,Department of Medicine, University of Udine, Udine, Italy
| | - Fabio Puglisi
- Department of Medical Oncology, IRCCS Centro di Riferimento Oncologico di Aviano (CRO), Aviano, Italy.,Department of Medicine, University of Udine, Udine, Italy
| | - Nicla La Verde
- Department of Oncology, ASST Fatebenefratelli Sacco - PO Luigi Sacco, Milan, Italy
| | - Grazia Arpino
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Andrea Rocca
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST, Meldola, Italy
| | | | - Rebecca Pedersini
- Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Medical Oncology, University of Brescia at ASST Spedali Civili, Brescia, Italy
| | - Alessandra Fabi
- Division of Medical Oncology, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Daniele Generali
- Department of Medical, Surgery and Health Sciences, University of Trieste, Trieste, Italy.,Breast Cancer Unit & Translational Research Unit, ASST Cremona, Cremona, Italy
| | - Agnese Losurdo
- Medical Oncology and Hematology Unit, Humanitas Clinical and Research Center - IRCCS, Rozzano, Milan, Italy
| | - Filippo Montemurro
- Multidisciplinary Oncology Outpatient Clinic, Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy
| | - Giuseppe Curigliano
- Division of Early Drug Development for Innovative Therapies, IEO, European Institute of Oncology IRCCS, Milan, Italy.,Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Lucia Del Mastro
- IRCCS Ospedale Policlinico San Martino, U.O.S.D. Breast Unit, Genova, Italy.,Dipartimento di Medicina Interna e Specialità Mediche (DiMI), School of Medicine, University of Genova, Genova, Italy
| | - Andrea Michelotti
- UO Oncologia Medica 2, Ospedale S. Chiara, Dipartimento di Oncologia, Dei Trapianti e Delle Nuove Tecnologie, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
| | - Enrico Cortesi
- Department of Medico-Surgical Sciences and Translational Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Valentina Guarneri
- Medical Oncology 2, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.,Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy
| | - Giancarlo Pruneri
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.,Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Luigi Mariani
- Unit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo de Braud
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.,Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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Rozenblit M, Mun S, Soulos P, Adelson K, Pusztai L, Mougalian S. Patterns of treatment with everolimus exemestane in hormone receptor-positive HER2-negative metastatic breast cancer in the era of targeted therapy. Breast Cancer Res 2021; 23:14. [PMID: 33514405 PMCID: PMC7844919 DOI: 10.1186/s13058-021-01394-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 01/17/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND There is currently no clinical trial data regarding the efficacy of everolimus exemestane (EE) following prior treatment with CDK4/6 inhibitors (CDK4/6i). This study assesses the use and efficacy of everolimus exemestane in patients with metastatic HR+ HER2- breast cancer previously treated with endocrine therapy (ET) or endocrine therapy + CDK4/6i. METHODS Retrospective analysis of electronic health record-derived data for HR+ HER2- metastatic breast cancer from 2012 to 2018. The proportion of patients receiving EE first-line, second-line, or third-line, and the median duration of EE prior to next line of treatment (TTNT) by line of therapy was calculated. OS for patients receiving EE first-line, second-line, or third-line, indexed to the date of first-line therapy initiation and stratified by prior treatment received, was calculated with Kaplan-Meier method with multivariable Cox proportional hazards regression analysis. RESULTS Six hundred twenty-two patients received EE first-line (n = 104, 16.7%), second-line (n = 273, 43.9%) or third-line (n = 245, 39.4%). Median TTNT was 8.3 months, 5.5 months, and 4.8 months respectively. Median TTNT of EE second-line was longer following prior ET alone compared to prior ET + CDK4/6i (6.2 months (95% CI 5.2, 7.3) vs 4.3 months (95% CI 3.2, 5.7) respectively, p = 0.03). Similarly, EE third-line following ET alone vs ET + CDK4/6i in first- or second-line resulted in median TTNT 5.6 months (95% CI 4.4, 6.9) vs 4.1 months (95% CI 3.6, 6.1) respectively, although this was not statistically significant (p = 0.08). Median OS was longer for patients who received EE following prior ET + CDK4/6i. EE second-line following ET + CDK 4/6i vs ET alone resulted in median OS 37.7 months vs. 32.7 months (p = 0.449). EE third-line following ET + CDK4/6i vs prior ET alone resulted in median OS 59.2 months vs. 40.8 months (p < 0.010). This difference in OS was not statistically significant when indexed to the start of EE therapy. CONCLUSION This study suggests that EE remains an effective treatment option after prior ET or ET + CDK4/6i use. Median TTNT of EE was longer for patients who received prior ET, whereas median OS was longer for patients who received prior ET + CDK4/6i. However, this improvement in OS was not statistically significant when indexed to the start of EE therapy suggesting that OS benefit is primarily driven by prior CDK4/6i use. EE remains an effective treatment option regardless of prior treatment option.
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Affiliation(s)
- Mariya Rozenblit
- Yale School of Medicine, 333 Cedar St., PO Box 208032, New Haven, CT, 05620, USA
| | - Sophia Mun
- Yale COPPER, Harkness Office Building, 367 Cedar Street, New Haven, CT, 06510, USA
| | - Pamela Soulos
- Yale COPPER, Harkness Office Building, 367 Cedar Street, New Haven, CT, 06510, USA
| | - Kerin Adelson
- Yale School of Medicine, 333 Cedar St., PO Box 208032, New Haven, CT, 05620, USA
| | - Lajos Pusztai
- Yale School of Medicine, 333 Cedar St., PO Box 208032, New Haven, CT, 05620, USA
| | - Sarah Mougalian
- Yale School of Medicine, 333 Cedar St., PO Box 208032, New Haven, CT, 05620, USA.
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Larsen LJ, Møller LB. Crosstalk of Hedgehog and mTORC1 Pathways. Cells 2020; 9:cells9102316. [PMID: 33081032 PMCID: PMC7603200 DOI: 10.3390/cells9102316] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 09/30/2020] [Accepted: 10/13/2020] [Indexed: 02/07/2023] Open
Abstract
Hedgehog (Hh) signaling and mTOR signaling, essential for embryonic development and cellular metabolism, are both coordinated by the primary cilium. Observations from cancer cells strongly indicate crosstalk between Hh and mTOR signaling. This hypothesis is supported by several studies: Evidence points to a TGFβ-mediated crosstalk; Increased PI3K/AKT/mTOR activity leads to increased Hh signaling through regulation of the GLI transcription factors; increased Hh signaling regulates mTORC1 activity positively by upregulating NKX2.2, leading to downregulation of negative mTOR regulators; GSK3 and AMPK are, as members of both signaling pathways, potentially important links between Hh and mTORC1 signaling; The kinase DYRK2 regulates Hh positively and mTORC1 signaling negatively. In contrast, both positive and negative regulation of Hh has been observed for DYRK1A and DYRK1B, which both regulate mTORC1 signaling positively. Based on crosstalk observed between cilia, Hh, and mTORC1, we suggest that the interaction between Hh and mTORC1 is more widespread than it appears from our current knowledge. Although many studies focusing on crosstalk have been carried out, contradictory observations appear and the interplay involving multiple partners is far from solved.
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Liu S, Sun X, Xu X, Lin F. Comparison of Endocrine Therapies in Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced or Metastatic Breast Cancer: A Network Meta-Analysis. J Breast Cancer 2020; 23:460-483. [PMID: 33154823 PMCID: PMC7604373 DOI: 10.4048/jbc.2020.23.e55] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 08/26/2020] [Indexed: 11/30/2022] Open
Abstract
We aimed to explore what kind of endocrine treatments are optimal for hormone receptor-positive and human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer in some specific clinical situations. We searched randomized controlled trials in Embase, Medline, the Cochrane library, and PubMed from inception to April 1, 2020 and performed a network meta-analysis based on a Bayesian fixed-effects model. Progression-free survival (PFS) with hazard ratios and corresponding 95% confidence interval was defined as the primary endpoint, while overall survival (OS), objective response rate (ORR), clinical benefit rate and serious adverse events were used as secondary endpoints. A total of 35 studies involving 12,285 patients and 24 treatment options were included. In general, most co-treatment options prolonged PFS compared to single-agent therapy, of which aromatase inhibitor (AI) plus everolimus and fulvestrant plus palbociclib were probably the most effective agents, and the latter had the best safety record. However, despite the superior efficacy of fulvestrant plus capecitabine for PFS and OS, palpable toxic effects have been demonstrated for this treatment, so its application must be scrupulously considered. The results of subgroup analysis indicated that fulvestrant combined with palbociclib improved prognosis for phosphatidylinositol 3-kinase (PI3K)-mutated patients, PI3K-unmutated patients, patients with endocrine therapy resistance, and visceral metastatic patients, while no obvious improvement was detected in OS. Moreover, the efficacy of fulvestrant plus cyclin-dependent kinase 4/6 (CDK4/6) inhibitors was slightly better than that of AI plus CDK4/6 inhibitors, while AI plus everolimus was more efficacious than fulvestrant combined with everolimus in terms of PFS, OS, and ORR. In conclusion, our results provide moderate evidence that fulvestrant plus palbociclib and AI plus everolimus were the most effective treatments, while the efficacy and safety of fulvestrant plus palbociclib was obviously superior in some specific clinical situations.
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Affiliation(s)
- Siqi Liu
- Department of Breast Surgery, Capital Medical University Electric Power Teaching Hospital, Beijing, China
| | - Xin Sun
- Department of Breast Surgery, Capital Medical University Electric Power Teaching Hospital, Beijing, China
| | - Xiaohui Xu
- Department of Breast Surgery, Capital Medical University Electric Power Teaching Hospital, Beijing, China
| | - Fangcai Lin
- Department of General Surgery, Capital Medical University Electric Power Teaching Hospital, Beijing, China
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Tsuji-Tamura K, Sato M, Fujita M, Tamura M. The role of PI3K/Akt/mTOR signaling in dose-dependent biphasic effects of glycine on vascular development. Biochem Biophys Res Commun 2020; 529:596-602. [DOI: 10.1016/j.bbrc.2020.06.085] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 06/17/2020] [Indexed: 12/21/2022]
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32
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Long L, Assaraf YG, Lei ZN, Peng H, Yang L, Chen ZS, Ren S. Genetic biomarkers of drug resistance: A compass of prognosis and targeted therapy in acute myeloid leukemia. Drug Resist Updat 2020; 52:100703. [PMID: 32599434 DOI: 10.1016/j.drup.2020.100703] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 04/22/2020] [Accepted: 04/27/2020] [Indexed: 12/17/2022]
Abstract
Acute myeloid leukemia (AML) is a highly aggressive hematological malignancy with complex heterogenous genetic and biological nature. Thus, prognostic prediction and targeted therapies might contribute to better chemotherapeutic response. However, the emergence of multidrug resistance (MDR) markedly impedes chemotherapeutic efficacy and dictates poor prognosis. Therefore, prior evaluation of chemoresistance is of great importance in therapeutic decision making and prognosis. In recent years, preclinical studies on chemoresistance have unveiled a compendium of underlying molecular basis, which facilitated the development of targetable small molecules. Furthermore, routing genomic sequencing has identified various genomic aberrations driving cellular response during the course of therapeutic treatment through adaptive mechanisms of drug resistance, some of which serve as prognostic biomarkers in risk stratification. However, the underlying mechanisms of MDR have challenged the certainty of the prognostic significance of some mutations. This review aims to provide a comprehensive understanding of the role of MDR in therapeutic decision making and prognostic prediction in AML. We present an updated genetic landscape of the predominant mechanisms of drug resistance with novel targeted therapies and potential prognostic biomarkers from preclinical and clinical chemoresistance studies in AML. We particularly highlight the unfolded protein response (UPR) that has emerged as a critical regulatory pathway in chemoresistance of AML with promising therapeutic horizon. Futhermore, we outline the most prevalent mutations associated with mechanisms of chemoresistance and delineate the future directions to improve the current prognostic tools. The molecular analysis of chemoresistance integrated with genetic profiling will facilitate decision making towards personalized prognostic prediction and enhanced therapeutic efficacy.
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MESH Headings
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Biomarkers, Tumor/antagonists & inhibitors
- Biomarkers, Tumor/genetics
- Disease-Free Survival
- Drug Resistance, Multiple/drug effects
- Drug Resistance, Multiple/genetics
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/mortality
- Molecular Targeted Therapy/methods
- Mutation
- Neoplasm Recurrence, Local/epidemiology
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/prevention & control
- Precision Medicine/methods
- Prognosis
- Unfolded Protein Response/genetics
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Affiliation(s)
- Luyao Long
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, P.R. China; Graduate School, Chinese Academy of Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China; Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, P.R. China
| | - Yehuda G Assaraf
- The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, 3200003, Israel
| | - Zi-Ning Lei
- College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA; School of Public Health, Guangzhou Medical University, Guangzhou, P.R. China
| | - Hongwei Peng
- Department of Pharmacy, First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
| | - Lin Yang
- Department of Hematology, the Second Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Zhe-Sheng Chen
- College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
| | - Simei Ren
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, P.R. China; Graduate School, Chinese Academy of Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China; Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, P.R. China.
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Abstract
Checkpoint inhibitors have become an efficient way to treat cancers. Indeed, anti-CTLA-4, anti-PD1, and anti-PDL-1 antibodies are now used as therapies for cancers. However, while these therapies are very efficient in certain tumors, they remain poorly efficient in others. This might be explained by the immune infiltrate, the expression of target molecules, and the influence of the tumor microenvironment. It is therefore critical to identify checkpoint antigens that represent alternative targets for immunotherapies. PVR-like molecules play regulatory roles in immune cell functions. These proteins are expressed by different cell types and have been shown to be upregulated in various malignancies. PVR and Nectin-2 are expressed by tumor cells as well as myeloid cells, while TIGIT, CD96, and DNAM-1 are expressed on effector lymphoid cells. PVR is able to bind DNAM-1, CD96, and TIGIT, which results in two distinct profiles of effector cell activation. Indeed, while binding to DNAM-1 induces the release of cytokines and cytotoxicity of cytotoxic effector cells, binding TIGIT induces an immunosuppressive and non-cytotoxic profile. PVR is also able to bind CD96, which induces an immunosuppressive response in murine models. Unfortunately, in humans, results remain contradictory, and this interaction might induce the activation or the suppression of the immune response. Similarly, Nectin-2 was shown to bind TIGIT and to induce regulatory profiles in effectors cells such as NK and T cells. Therefore, these data highlight the potential of each of the molecules of the “PVR–TIGIT axis” as a potential target for immune checkpoint therapy. However, many questions remain to be answered to fully understand the mechanisms of this synapse, in particular for human CD96 and Nectin-2, which are still understudied. Here, we review the recent advances in “PVR–TIGIT axis” research and discuss the potential of targeting this axis by checkpoint immunotherapies.
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Affiliation(s)
- Laurent Gorvel
- Cancer Research Center of Marseille, INSERM U1068, CNRS U7258, Aix Marseille Université, Institut Paoli - Calmettes, Marseille, France
| | - Daniel Olive
- Cancer Research Center of Marseille, INSERM U1068, CNRS U7258, Aix Marseille Université, Institut Paoli - Calmettes, Marseille, France
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