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Gao J, Wang Y, Wang R, Liu M, Wang H, Li J, Du J. Preclinical studies of a PARP-targeted theranostic radiopharmaceutical for pancreatic cancer. Front Pharmacol 2025; 16:1576587. [PMID: 40444043 PMCID: PMC12119578 DOI: 10.3389/fphar.2025.1576587] [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: 02/14/2025] [Accepted: 03/17/2025] [Indexed: 06/02/2025] Open
Abstract
Objective This study aims to improve the biodistribution of probes and enhance tumor targeting through 68Ga/177Lu-labeled optimized probes, thereby providing better tumor detection and assessment in PET imaging while also exploring their therapeutic effects on tumors. Methods The physicochemical properties of PARPi probes were optimized through polyethylene glycol (PEG) modification. The tumor inhibition effect of the novel probes was validated through the assessment of in vitro affinity, uptake, in vivo distribution, and tumor targeting of the PARPi probes. Based on the distribution results, OLINDA/EXM radiation dose estimation was then performed to optimize the clinically administered dose. Results In the study, a novel PARP-targeted imaging agent, DOTA-PEG-PARPi, was designed and optimized, demonstrating sufficient in vivo stability. The results of in vitro trials showed strong affinity and uptake of PEG-PARPi in pancreatic cancer tumor cells. SPECT/CT imaging revealed significant radioactive accumulation, notable uptake, and prolonged retention time in PSN-1 tumors. Tissue distribution results showed that tumor uptake peaked 3 h after administration. According to dose estimation, the highest absorbed dose was observed in the pancreas of female adults. Conclusion The PEG-modified PARPi probe not only retained high affinity and targeting capability but also significantly improved retention time during in vivo trials.
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Affiliation(s)
- Jie Gao
- China Institute of Atomic Energy, Beijing, China
- China Institute for Radiation Protection/National Atomic Energy Agency Nuclear Technology (Nonclinical Evaluation of Radiopharmaceuticals) Research and Development Center/CNNC Key Laboratory on Radiotoxicology and Radiopharmaceutical Preclinical Evaluation, Taiyuan, Shanxi, China
| | - Yuhao Wang
- China Institute for Radiation Protection/National Atomic Energy Agency Nuclear Technology (Nonclinical Evaluation of Radiopharmaceuticals) Research and Development Center/CNNC Key Laboratory on Radiotoxicology and Radiopharmaceutical Preclinical Evaluation, Taiyuan, Shanxi, China
| | - Ruoqi Wang
- China Institute for Radiation Protection/National Atomic Energy Agency Nuclear Technology (Nonclinical Evaluation of Radiopharmaceuticals) Research and Development Center/CNNC Key Laboratory on Radiotoxicology and Radiopharmaceutical Preclinical Evaluation, Taiyuan, Shanxi, China
| | - Mengya Liu
- China Institute of Atomic Energy, Beijing, China
- China Institute for Radiation Protection/National Atomic Energy Agency Nuclear Technology (Nonclinical Evaluation of Radiopharmaceuticals) Research and Development Center/CNNC Key Laboratory on Radiotoxicology and Radiopharmaceutical Preclinical Evaluation, Taiyuan, Shanxi, China
| | - Hongliang Wang
- First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jianguo Li
- China Institute for Radiation Protection/National Atomic Energy Agency Nuclear Technology (Nonclinical Evaluation of Radiopharmaceuticals) Research and Development Center/CNNC Key Laboratory on Radiotoxicology and Radiopharmaceutical Preclinical Evaluation, Taiyuan, Shanxi, China
| | - Jin Du
- China Institute of Atomic Energy, Beijing, China
- China Isotope and Radiation Corporation, Beijing, China
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2
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Panda SM, Nandeshwar, Tripathy U. In silico screening and identifying phytoconstituents of Withania somnifera as potent inhibitors of BRCA1 mutants: A therapeutic against breast cancer. Int J Biol Macromol 2024; 282:136977. [PMID: 39490493 DOI: 10.1016/j.ijbiomac.2024.136977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 07/25/2024] [Accepted: 10/25/2024] [Indexed: 11/05/2024]
Abstract
Breast CAncer gene 1 (BRCA1) is an anti-oncogene that helps the cell repair damaged DNA and preserve genetic material. BRCA1 also acts as a cell growth suppressor and produces tumor suppressor gene (TSG) proteins, i.e., BRCA1 protein. Remarkably, BRCA1 mutations account for 90 % of hereditary breast cancer and a majority of hereditary ovarian cancer. Hence, we have considered three mutants of BRCA1 (R1699W, R1699Q, T1700A) in this study and adopted an in-silico approach to find the best possible phytochemical to inhibit these mutated proteins, enabling early breast cancer diagnosis. Perceiving the importance, many natural molecules from ancient medicinal plants are considered for molecular docking. Our findings suggest that though many molecules bind actively with the receptor's active site, the top three phytoconstituents (27-Deoxy-14-hydroxywithaferin A, Withacoagulin, Somniferanolide) of Withania somnifera, commonly known as Ashwagandha, have high binding affinities and suitable pharmacokinetic properties, making these natural compounds potential drug candidates. Further, molecular dynamics (MD) simulation and the binding free energy calculation show stability and thermodynamically favourable. We can, therefore, draw the conclusion that these lead compounds act as potential inhibitors against BRCA1. However, wet lab experiments and clinical trials are recommended to ascertain its efficacy, hence the development of novel BRCA1 inhibitors.
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Affiliation(s)
- Smita Manjari Panda
- Department of Physics, Indian Institute of Technology (Indian School of Mines), Dhanbad 826004, Jharkhand, India
| | - Nandeshwar
- Department of Physics, Indian Institute of Technology (Indian School of Mines), Dhanbad 826004, Jharkhand, India
| | - Umakanta Tripathy
- Department of Physics, Indian Institute of Technology (Indian School of Mines), Dhanbad 826004, Jharkhand, India.
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3
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Dewani D, Jaiswal A, Karwade P. Poly(Adenosine Diphosphate Ribose) Polymerase (PARP) Inhibitors in the Treatment of Advanced Ovarian Cancer: A Narrative Review. Cureus 2024; 16:e68463. [PMID: 39360040 PMCID: PMC11446491 DOI: 10.7759/cureus.68463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 09/02/2024] [Indexed: 10/04/2024] Open
Abstract
Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors have appeared as a revolutionary approach to treating advanced ovarian cancer, particularly in patients with breast cancer (BRCA) mutations and homologous recombination deficiency (HRD). This narrative review explores PARP inhibitors' clinical efficiency, safety, and changing role in this context. PARP inhibitors, such as olaparib, niraparib, or rucaparib, provide considerable benefits regarding progression-free survival expansion and overall outcomes improvement in first-line maintenance and recurrent settings. The underlying mechanisms, patient selection criteria, and resistance patterns are discussed, alongside insights into combination therapies to overcome resistance and enhance therapeutic efficacy. Ongoing clinical trials and future potential for personalized therapy approaches using PARP inhibitors for advanced ovarian cancer are also highlighted. However, despite these drugs' phenomenal ability to revolutionize treatment protocols for such cancer types, several challenges remain: toxicity management, cost, and development of resistance will require more research to optimize their use or broaden patient populations who can benefit from them.
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Affiliation(s)
- Deepika Dewani
- Obstetrics and Gynaecology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Arpita Jaiswal
- Obstetrics and Gynaecology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Pravin Karwade
- Obstetrics and Gynaecology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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Gralewska P, Gajek A, Marczak A, Rogalska A. Targeted Nanocarrier-Based Drug Delivery Strategies for Improving the Therapeutic Efficacy of PARP Inhibitors against Ovarian Cancer. Int J Mol Sci 2024; 25:8304. [PMID: 39125873 PMCID: PMC11312858 DOI: 10.3390/ijms25158304] [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: 06/19/2024] [Revised: 07/20/2024] [Accepted: 07/28/2024] [Indexed: 08/12/2024] Open
Abstract
The current focus of ovarian cancer (OC) research is the improvement of treatment options through maximising drug effectiveness. OC remains the fifth leading cause of cancer-induced mortality in women worldwide. In recent years, nanotechnology has revolutionised drug delivery systems. Nanoparticles may be utilised as carriers in gene therapy or to overcome the problem of drug resistance in tumours by limiting the number of free drugs in circulation and thereby minimising undesired adverse effects. Cell surface receptors, such as human epidermal growth factor 2 (HER2), folic acid (FA) receptors, CD44 (also referred to as homing cell adhesion molecule, HCAM), and vascular endothelial growth factor (VEGF) are highly expressed in ovarian cancer cells. Generation of active targeting nanoparticles involves modification with ligands that recognise cell surface receptors and thereby promote internalisation by cancer cells. Several poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are currently used for the treatment of high-grade serous ovarian carcinomas (HGSOC) or platinum-sensitive relapsed OC. However, PARP resistance and poor drug bioavailability are common challenges, highlighting the urgent need to develop novel, effective strategies for ovarian cancer treatment. This review evaluates the utility of nanoparticles in ovarian cancer therapy, with a specific focus on targeted approaches and the use of PARPi nanocarriers to optimise treatment outcomes.
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Affiliation(s)
| | | | | | - Aneta Rogalska
- Department of Medical Biophysics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90–236 Lodz, Poland; (P.G.); (A.G.); (A.M.)
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5
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Chaudhary M, Kumar S, Kaur P, Sahu SK, Mittal A. Comprehensive Review on Recent Strategies for Management of Prostate Cancer: Therapeutic Targets and SAR. Mini Rev Med Chem 2024; 24:721-747. [PMID: 37694781 DOI: 10.2174/1389557523666230911141339] [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: 05/23/2023] [Revised: 07/09/2023] [Accepted: 07/18/2023] [Indexed: 09/12/2023]
Abstract
Prostate cancer is a disease that is affecting a large population worldwide. Androgen deprivation therapy (ADT) has become a foundation for the treatment of advanced prostate cancer, as used in most clinical settings from neo-adjuvant to metastatic stage. In spite of the success of ADT in managing the disease in the majority of men, hormonal manipulation fails eventually. New molecules are developed for patients with various hormone-refractory diseases. Advancements in molecular oncology have increased understanding of numerous cellular mechanisms which control cell death in the prostate and these insights can lead to the development of more efficacious and tolerable therapies for carcinoma of the prostate. This review is focused on numerous therapies that might be a boon for prostate therapy like signaling inhibitors, vaccines, and inhibitors of androgen receptors. Along with these, various bioactive molecules and their derivatives are highlighted, which act as potential antiprostate cancer agents. This article also emphasized the recent advances in the field of medicinal chemistry of prostate cancer agents.
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Affiliation(s)
- Manish Chaudhary
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road, Phagwara, Punjab, 144001, India
| | - Shubham Kumar
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road, Phagwara, Punjab, 144001, India
| | - Paranjeet Kaur
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Sanjeev Kumar Sahu
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road, Phagwara, Punjab, 144001, India
| | - Amit Mittal
- Faculty of Pharmaceutical Sciences, Desh Bhagat University, Amloh Road, Mandi Gobindgarh, Punjab, 147301, India
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Zhang Q, Ding Y, Shu Y, Chen J. A real-world disproportionality analysis of Rucaparib: Post-marketing Pharmacovigilance Data. BMC Cancer 2023; 23:745. [PMID: 37568126 PMCID: PMC10416473 DOI: 10.1186/s12885-023-11201-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 07/20/2023] [Indexed: 08/13/2023] Open
Abstract
BACKGROUND Rucaparib has been approved for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. However, the long-term safety of rucaparib in large sample population was unknown. The presented study aimed to evaluate rucaparib-associated adverse events (AEs) according to the real-world pharmacovigilance database. METHODS Disproportionality analysis was conducted to assess the association between rucaparib and its AEs. Data were collected from the international pharmacovigilance database of US FDA Adverse Event Reporting System (FAERS) between January 2017 and June 2022. The characteristics of rucaparib-related AEs, and the onset time were further analyzed. RESULTS A total of 9,296,694 AE reports were recorded in the FAERS during the study period, among which 7,087 reports were associated with rucaparib. About 135 rucaparib-related AE signals in 15 system organ class (SOCs) were identified. The most common AEs included anaemia, thrombocytopenia, nausea, vomiting, fatigue, blood creatinine increase, alanine aminotransferase increase, and aspartate aminotransferase increase, which were listed in the label for rucaparib. Of note, 21 new and unexpected significant AEs that off-label were also found in our study, such as preferred term (PTs) of intestinal obstruction, gastrooesophageal reflux disease, blood iron decreased, dehydration, and hypersomnia. The median onset time of rucaparib-related AEs was 12 days (interquartile range [IQR] 1-62 days), and had early failure types. CONCLUSION Our study demonstrated potential new AEs of rucaparib, and further studies were expected to confirm the results.
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Affiliation(s)
- Qilin Zhang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yiling Ding
- Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, 113-0033, Japan
| | - Yamin Shu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China.
| | - Jing Chen
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No.1095 Jiefang Avenue, Wuhan, 430030, China.
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Lu T, Li T, Wu MK, Zheng CC, He XM, Zhu HL, Li L, Man RJ. Molecular simulations required to target novel and potent inhibitors of cancer invasion. Expert Opin Drug Discov 2023; 18:1367-1377. [PMID: 37676052 DOI: 10.1080/17460441.2023.2254695] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 08/30/2023] [Indexed: 09/08/2023]
Abstract
INTRODUCTION Computer-aided drug design (CADD) is a computational approach used to discover, develop, and analyze drugs and active molecules with similar biochemical properties. Molecular simulation technology has significantly accelerated drug research and reduced manufacturing costs. It is an optimized drug discovery method that greatly improves the efficiency of novel drug development processes. AREASCOVERED This review discusses the development of molecular simulations of effective cancer inhibitors and traces the main outcomes of in silico studies by introducing representative categories of six important anticancer targets. The authors provide views on this topic from the perspective of both medicinal chemistry and artificial intelligence, indicating the major challenges and predicting trends. EXPERT OPINION The goal of introducing CADD into cancer treatment is to realize a highly efficient, accurate, and desired approach with a high success rate for identifying potent drug candidates. However, the major challenge is the lack of a sophisticated data-filtering mechanism to verify bottom data from mixed-quality references. Consequently, despite the continuous development of algorithms, computer power, and interface optimization, specific data filtering mechanisms will become an urgent and crucial issue in the future.
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Affiliation(s)
| | - Tong Li
- Guangxi Key Laboratory for Polysaccharide Materials and Modifications, Guangxi University for Nationalities, Nanning, China
| | - Meng-Ke Wu
- Guangxi Key Laboratory for Polysaccharide Materials and Modifications, Guangxi University for Nationalities, Nanning, China
| | - Chi-Chong Zheng
- Guangxi Key Laboratory for Polysaccharide Materials and Modifications, Guangxi University for Nationalities, Nanning, China
| | - Xue-Mei He
- Agro-food Science and Technology Research Institute, Guangxi Academy of Agricultural Science, Nanning, China
| | - Hai-Liang Zhu
- School of Life Sciences, Nanjing University, Nanjing, China
| | - Li Li
- Agro-food Science and Technology Research Institute, Guangxi Academy of Agricultural Science, Nanning, China
| | - Ruo-Jun Man
- Guangxi Key Laboratory for Polysaccharide Materials and Modifications, Guangxi University for Nationalities, Nanning, China
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8
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Lin C, Liu P, Shi C, Qiu L, Shang D, Lu Z, Tu Z, Liu H. Therapeutic targeting of DNA damage repair pathways guided by homologous recombination deficiency scoring in ovarian cancers. Fundam Clin Pharmacol 2023; 37:194-214. [PMID: 36130021 DOI: 10.1111/fcp.12834] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 07/23/2022] [Accepted: 09/20/2022] [Indexed: 12/01/2022]
Abstract
The susceptibility of cells to DNA damage and their DNA repair ability are crucial for cancer therapy. Homologous recombination is one of the major repairing mechanisms for DNA double-strand breaks. Approximately half of ovarian cancer (OvCa) cells harbor homologous recombination deficiency (HRD). Considering that HRD is a major hallmark of OvCas, scholars proposed HRD scoring to evaluate the HRD degree and guide the choice of therapeutic strategies for OvCas. In the last decade, synthetic lethal strategy by targeting poly (ADP-ribose) polymerase (PARP) in HR-deficient OvCas has attracted considerable attention in view of its favorable clinical effort. We therefore suggested that the uses of other DNA damage/repair-targeted drugs in HR-deficient OvCas might also offer better clinical outcome. Here, we reviewed the current small molecule compounds that targeted DNA damage/repair pathways and discussed the HRD scoring system to guide their clinical uses.
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Affiliation(s)
- Chunxiu Lin
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Peng Liu
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Chaowen Shi
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Lipeng Qiu
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Dongsheng Shang
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Ziwen Lu
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Zhigang Tu
- School of Life Sciences, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Hanqing Liu
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, China
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Schutte T, Embaby A, Steeghs N, van der Mierden S, van Driel W, Rijlaarsdam M, Huitema A, Opdam F. Clinical development of WEE1 inhibitors in gynecological cancers: A systematic review. Cancer Treat Rev 2023; 115:102531. [PMID: 36893690 DOI: 10.1016/j.ctrv.2023.102531] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/24/2023] [Accepted: 02/26/2023] [Indexed: 03/06/2023]
Abstract
INTRODUCTION The anti-tumor activity of WEE1 inhibitors (WEE1i) in gynecological malignancies has recently been demonstrated in clinical trials and its rationale is based on biological/molecular features of gynecological cancers. With this systematic review, we aim to outline the clinical development and current evidence regarding the efficacy and safety of these targeted agents in in this patient group. METHODS Systematic literature review of trials including patients with gynecological cancers treated with a WEE1i. The primary objective was to summarize the efficacy of WEE1i in gynecological malignancies regarding objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS) and progression-free survival (PFS). Secondary objectives included toxicity profile, Maximum Tolerated Dose (MTD), pharmacokinetics, drug-drug interactions and exploratory objectives such as biomarkers for response. RESULTS 26 records were included for data extraction. Almost all trials used the first-in-class WEE1i adavosertib; one conference abstract reported about Zn-c3. The majority of the trials included diverse solid tumors (n = 16). Six records reported efficacy results of WEE1i in gynecological malignancies (n = 6). Objective response rates of adavosertib monotherapy or in combination with chemotherapy ranged between 23% and 43% in these trials. Median PFS ranged from 3.0 to 9.9 months. The most common adverse events were bone marrow suppression, gastrointestinal toxicities and fatigue. Mainly alterations in cell cycle regulator genes TP53 and CCNE1 were potential predictors of response. CONCLUSION This report summarizes encouraging clinical development of WEE1i in gynecological cancers and considers its application in future studies. Biomarker-driven patient selection might be essential to increase the response rates.
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Affiliation(s)
- Tim Schutte
- Department of Internal Medicine and Department of Medical Oncology, Amsterdam UMC, Location VUmc, Amsterdam, Netherlands.
| | - Alaa Embaby
- Department of Clinical Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, Netherlands
| | - Neeltje Steeghs
- Department of Medical Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, Netherlands
| | - Stevie van der Mierden
- Scientific Information Service, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Willemien van Driel
- Department of Gynecological Oncology, The Netherlands Cancer Insitute - Antoni van Leeuwenhoek, Amsterdam, Netherlands
| | - Martin Rijlaarsdam
- Department of Medical Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, Netherlands
| | - Alwin Huitema
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, Netherlands; Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands; Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Frans Opdam
- Department of Medical Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, Netherlands
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Implementation of Comprehensive Genomic Profiling in Ovarian Cancer Patients: A Retrospective Analysis. Cancers (Basel) 2022; 15:cancers15010218. [PMID: 36612212 PMCID: PMC9818378 DOI: 10.3390/cancers15010218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 12/17/2022] [Accepted: 12/26/2022] [Indexed: 12/31/2022] Open
Abstract
Comprehensive genomic profiling (CGP) allows for the detection of driver alterations at high resolution, but the limited number of approved targeted therapies and their high costs have contributed to its limited clinical utilization. We retrospectively compared data of 946 women with ovarian cancer (11.4% were referred to CGP, and 88.6% served as control) to examine whether CGP provides a prognosis benefit. Patient baseline parameters were similar between the groups. Cox regression analysis adjusted for age, disease stage at diagnosis, and recurrence status showed statistically significantly longer median overall survival (mOS) in the CGP group versus the control (73.4 versus 54.5 months, p < 0.001). Fifty-four patients (52.9%) had actionable mutations with potential treatments; twenty-six (48.2%) were treated with matched targeted therapy, showing a trend for longer mOS than the eighty-six women in the CGP group who were not given a suggested treatment (105.5 versus 63.6 months, p = 0.066). None of the genomic alterations predicted metastasis location. CCNE1 amplification and KRAS mutations were associated with shorter mOS. Patients with tumor mutation burden ≥4 mutations/megabase had longer mOS. High loss of heterozygosity was associated with longer mOS (99.0 versus 48.2 months, p = 0.004). CGP testing may provide both prognostic and predictive insights for treatment of patients with ovarian cancer. Prospective studies of larger cohorts are warranted.
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Yaragorla S, Arun D. Arylation and Aryne Insertion into C-Acylimines: A Simple, Flexible, and Divergent Synthesis of C2-Aryl Indoles. J Org Chem 2022; 87:14250-14263. [PMID: 36219251 DOI: 10.1021/acs.joc.2c01753] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
We reveal a direct strategy for the flexible synthesis of C2-aryl/heteroaryl indoles without transition metal catalysts. The synthesis involves a one-pot, four-component reaction of readily available starting materials to offer diversity around the indole moiety with a broad substrate scope and high yields. The reaction proceeds via the Friedel-Crafts C-arylation of C-acylimine formed in situ, followed by N-arylation with aryne, a formal [3+2] cycloaddition, and a subsequent aromatization cascade.
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Affiliation(s)
- Srinivasarao Yaragorla
- School of Chemistry, University of Hyderabad, P.O. Central University, Hyderabad 500046, India
| | - Doma Arun
- School of Chemistry, University of Hyderabad, P.O. Central University, Hyderabad 500046, India
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12
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Pan C, Chen L, Zhang X, Zhang D, Song Q, Peng J, Li Q. Molecular insight into the
π‐stacking
interactions of human ovarian cancer
PARP
‐1 with its small‐molecule inhibitors and rational design of aromatic amino acid‐rich peptides to target
PARP
‐1 based on the
π‐stacking
network. J CHIN CHEM SOC-TAIP 2022. [DOI: 10.1002/jccs.202200004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Chunxia Pan
- Department of Gynecological Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan China
| | - Lei Chen
- Department of Gynecological Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan China
| | - Xinxin Zhang
- Department of Gynecological Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan China
| | - Depu Zhang
- Department of Gynecological Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan China
| | - Quqing Song
- Department of Gynecological Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan China
| | - Jingwei Peng
- Department of Gynecological Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan China
| | - Qingshui Li
- Department of Gynecological Oncology, Shandong Cancer Hospital and Institute Shandong First Medical University and Shandong Academy of Medical Sciences Jinan China
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13
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Sha H, Gan Y, Zou R, Wu J, Feng J. Research Advances in the Role of the Poly ADP Ribose Polymerase Family in Cancer. Front Oncol 2022; 11:790967. [PMID: 34976832 PMCID: PMC8716401 DOI: 10.3389/fonc.2021.790967] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 11/24/2021] [Indexed: 12/27/2022] Open
Abstract
Poly ADP ribose polymerases (PARPs) catalyze the modification of acceptor proteins, DNA, or RNA with ADP-ribose, which plays an important role in maintaining genomic stability and regulating signaling pathways. The rapid development of PARP1/2 inhibitors for the treatment of ovarian and breast cancers has advanced research on other PARP family members for the treatment of cancer. This paper reviews the role of PARP family members (except PARP1/2 and tankyrases) in cancer and the underlying regulatory mechanisms, which will establish a molecular basis for the clinical application of PARPs in the future.
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Affiliation(s)
- Huanhuan Sha
- Department of Chemotherapy, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Yujie Gan
- Department of Chemotherapy, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Renrui Zou
- Department of Chemotherapy, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Jianzhong Wu
- Research Center of Clinical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Jifeng Feng
- Department of Chemotherapy, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
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14
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Lai Z, Brosnan M, Sokol ES, Xie M, Dry JR, Harrington EA, Barrett JC, Hodgson D. Landscape of homologous recombination deficiencies in solid tumours: analyses of two independent genomic datasets. BMC Cancer 2022; 22:13. [PMID: 34979999 PMCID: PMC8722117 DOI: 10.1186/s12885-021-09082-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 11/24/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND DNA repair deficiencies are characteristic of cancer and homologous recombination deficiency (HRD) is the most common. HRD sensitizes tumour cells to PARP inhibitors so it is important to understand the landscape of HRD across different solid tumour types. METHODS Germline and somatic BRCA mutations in breast and ovarian cancers were evaluated using sequencing data from The Cancer Genome Atlas (TCGA) database. Secondly, a larger independent genomic dataset was analysed to validate the TCGA results and determine the frequency of germline and somatic mutations across 15 different candidate homologous recombination repair (HRR) genes, and their relationship with the genetic events of bi-allelic loss, loss of heterozygosity (LOH) and tumour mutation burden (TMB). RESULTS Approximately one-third of breast and ovarian cancer BRCA mutations were somatic. These showed a similar degree of bi-allelic loss and clinical outcomes to germline mutations, identifying potentially 50% more patients that may benefit from precision treatments. HRR mutations were present in sizable proportions in all tumour types analysed and were associated with high TMB and LOH scores. We also identified numerous BRCA reversion mutations across all tumour types. CONCLUSIONS Our results will facilitate future research into the efficacy of precision oncology treatments, including PARP and immune checkpoint inhibitors.
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Affiliation(s)
| | | | | | | | - Jonathan R Dry
- AstraZeneca, Waltham, MA, 02451, USA
- Present Address: Tempus Labs Inc., Boston, MA, USA
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15
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Tserpeli V, Stergiopoulou D, Londra D, Giannopoulou L, Buderath P, Balgkouranidou I, Xenidis N, Grech C, Obermayr E, Zeillinger R, Pavlakis K, Rampias T, Kakolyris S, Kasimir-Bauer S, Lianidou ES. Prognostic Significance of SLFN11 Methylation in Plasma Cell-Free DNA in Advanced High-Grade Serous Ovarian Cancer. Cancers (Basel) 2021; 14:cancers14010004. [PMID: 35008168 PMCID: PMC8750111 DOI: 10.3390/cancers14010004] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/08/2021] [Accepted: 12/16/2021] [Indexed: 12/24/2022] Open
Abstract
Background: Epigenetic alterations in ctDNA are highly promising as a source of novel potential liquid biopsy biomarkers and comprise a very promising liquid biopsy approach in ovarian cancer, for early diagnosis, prognosis and response to treatment. Methods: In the present study, we examined the methylation status of six gene promoters (BRCA1, CST6, MGMT, RASSF10, SLFN11 and USP44) in high-grade serous ovarian cancer (HGSOC). We evaluated the prognostic significance of DNA methylation of these six gene promoters in primary tumors (FFPEs) and plasma cfDNA samples from patients with early, advanced and metastatic HGSOC. Results: We report for the first time that the DNA methylation of SLFN11 in plasma cfDNA was significantly correlated with worse PFS (p = 0.045) in advanced stage HGSOC. Conclusions: Our results strongly indicate that SLFN11 epigenetic inactivation could be a predictor of resistance to platinum drugs in ovarian cancer. Our results should be further validated in studies based on a larger cohort of patients, in order to further explore whether the DNA methylation of SLFN11 promoter could serve as a potential prognostic DNA methylation biomarker and a predictor of resistance to platinum-based chemotherapy in ovarian cancer.
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Affiliation(s)
- Victoria Tserpeli
- Analysis of Circulating Tumor Cells, Lab of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece; (V.T.); (D.S.); (D.L.); (L.G.)
| | - Dimitra Stergiopoulou
- Analysis of Circulating Tumor Cells, Lab of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece; (V.T.); (D.S.); (D.L.); (L.G.)
| | - Dora Londra
- Analysis of Circulating Tumor Cells, Lab of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece; (V.T.); (D.S.); (D.L.); (L.G.)
| | - Lydia Giannopoulou
- Analysis of Circulating Tumor Cells, Lab of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece; (V.T.); (D.S.); (D.L.); (L.G.)
| | - Paul Buderath
- Department of Gynecology and Obstetrics, University Hospital of Essen, University of Duisburg-Essen, Hufelandstrasse 55, D-45122 Essen, Germany; (P.B.); (S.K.-B.)
| | - Ioanna Balgkouranidou
- Department of Oncology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (I.B.); (N.X.); (S.K.)
| | - Nikolaos Xenidis
- Department of Oncology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (I.B.); (N.X.); (S.K.)
| | - Christina Grech
- Department of Obstetrics and Gynecology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (E.O.); (R.Z.)
| | - Eva Obermayr
- Department of Obstetrics and Gynecology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (E.O.); (R.Z.)
| | - Robert Zeillinger
- Department of Obstetrics and Gynecology, Medical University of Vienna, 1090 Vienna, Austria; (C.G.); (E.O.); (R.Z.)
| | - Kitty Pavlakis
- Pathology Department, IASO Women’s Hospital, 15123 Athens, Greece;
| | - Theodoros Rampias
- Basic Research Center, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece;
| | - Stylianos Kakolyris
- Department of Oncology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece; (I.B.); (N.X.); (S.K.)
| | - Sabine Kasimir-Bauer
- Department of Gynecology and Obstetrics, University Hospital of Essen, University of Duisburg-Essen, Hufelandstrasse 55, D-45122 Essen, Germany; (P.B.); (S.K.-B.)
| | - Evi S. Lianidou
- Analysis of Circulating Tumor Cells, Lab of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece; (V.T.); (D.S.); (D.L.); (L.G.)
- Correspondence: ; Tel.: +30-210-7274311
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16
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Jeong KY, Park M. Poly adenosine diphosphate-ribosylation, a promising target for colorectal cancer treatment. World J Gastrointest Oncol 2021. [PMID: 34163574 DOI: 10.4251/wjgo.v13.i6.574.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The development of colorectal cancer (CRC) can result from changes in a variety of cellular systems within the tumor microenvironment. Particularly, it is primarily associated with genomic instability that is the gradual accumulation of genetic and epigenetic changes consisting of a characteristic set of mutations crucial for pathways in CRC progression. Based on this background, the potential to focus on poly [adenosine diphosphate (ADP)-ribose] polymerase (PARP)-1 and poly-ADP ribosylation (PARylation) as the main causes of malignant formation of CRC may be considered. One of the important functions of PARP-1 and PARylation is its deoxyribonucleic acid (DNA) repair function, which plays a pivotal role in the DNA damage response and prevention of DNA damage maintaining the redox homeostasis involved in the regulation of oxidation and superoxide. PARP-1 and PARylation can also alter epigenetic markers and chromatin structure involved in transcriptional regulation for the oncogenes or tumor suppressor genes by remodeling histone and chromatin enzymes. Given the high importance of these processes in CRC, it can be considered that PARP-1 and PARylation are at the forefront of the pathological changes required for CRC progression. Therefore, this review addresses the current molecular biological features for understanding the multifactorial function of PARP-1 and PARylation in CRC related to the aforementioned roles; furthermore, it presents a summary of recent approaches with PARP-1 inhibition in non-clinical and clinical studies targeting CRC. This understanding could help embrace the importance of targeting PARP-1 and PARylation in the treatment of CRC, which may present the potential to identify various research topics that can be challenged both non-clinically and clinically.
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Affiliation(s)
- Keun-Yeong Jeong
- Research and Development, Metimedi Pharmaceuticals, Incheon 22006, South Korea.
| | - Minhee Park
- Research and Development, Metimedi Pharmaceuticals, Incheon 22006, South Korea
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17
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Jeong KY, Park M. Poly adenosine diphosphate-ribosylation, a promising target for colorectal cancer treatment. World J Gastrointest Oncol 2021; 13:574-588. [PMID: 34163574 PMCID: PMC8204356 DOI: 10.4251/wjgo.v13.i6.574] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/22/2021] [Accepted: 05/08/2021] [Indexed: 02/06/2023] Open
Abstract
The development of colorectal cancer (CRC) can result from changes in a variety of cellular systems within the tumor microenvironment. Particularly, it is primarily associated with genomic instability that is the gradual accumulation of genetic and epigenetic changes consisting of a characteristic set of mutations crucial for pathways in CRC progression. Based on this background, the potential to focus on poly [adenosine diphosphate (ADP)-ribose] polymerase (PARP)-1 and poly-ADP ribosylation (PARylation) as the main causes of malignant formation of CRC may be considered. One of the important functions of PARP-1 and PARylation is its deoxyribonucleic acid (DNA) repair function, which plays a pivotal role in the DNA damage response and prevention of DNA damage maintaining the redox homeostasis involved in the regulation of oxidation and superoxide. PARP-1 and PARylation can also alter epigenetic markers and chromatin structure involved in transcriptional regulation for the oncogenes or tumor suppressor genes by remodeling histone and chromatin enzymes. Given the high importance of these processes in CRC, it can be considered that PARP-1 and PARylation are at the forefront of the pathological changes required for CRC progression. Therefore, this review addresses the current molecular biological features for understanding the multifactorial function of PARP-1 and PARylation in CRC related to the aforementioned roles; furthermore, it presents a summary of recent approaches with PARP-1 inhibition in non-clinical and clinical studies targeting CRC. This understanding could help embrace the importance of targeting PARP-1 and PARylation in the treatment of CRC, which may present the potential to identify various research topics that can be challenged both non-clinically and clinically.
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Affiliation(s)
- Keun-Yeong Jeong
- Research and Development, Metimedi Pharmaceuticals, Incheon 22006, South Korea
| | - Minhee Park
- Research and Development, Metimedi Pharmaceuticals, Incheon 22006, South Korea
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18
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Alvarez Secord A, O'Malley DM, Sood AK, Westin SN, Liu JF. Rationale for combination PARP inhibitor and antiangiogenic treatment in advanced epithelial ovarian cancer: A review. Gynecol Oncol 2021; 162:482-495. [PMID: 34090705 DOI: 10.1016/j.ygyno.2021.05.018] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 05/20/2021] [Indexed: 12/30/2022]
Abstract
Inhibitors of poly(ADP-ribose) polymerase (PARP) and angiogenesis have demonstrated single-agent activity in women with advanced ovarian cancer. Recent studies have aimed to establish whether combination therapy can augment the response seen with PARP inhibitors or antiangiogenic agents alone. This review provides an overview of PARP inhibitors and antiangiogenics as monotherapy in women with advanced ovarian cancer, explores potential mechanisms of action of PARP inhibitor and antiangiogenic combination treatments, reviews efficacy and safety data from trials evaluating this combination, and outlines ongoing and future trials evaluating this combination, discussing these in the context of the current and future treatment landscape for women with advanced ovarian cancer. Sentinel studies evaluating PARP inhibitor (n = 8), antiangiogenic (n = 4), and combination (n = 7) therapy were identified in women with newly diagnosed (n = 7) and recurrent (n = 12) ovarian cancer. PARP inhibitors included olaparib (n = 9), niraparib (n = 4), rucaparib (n = 1), and veliparib (n = 1). Antiangiogenic agents included bevacizumab (n = 7) and cediranib (n = 4). PARP inhibitors combined with antiangiogenics demonstrated efficacy based on objective response rates and progression-free survival (PFS) in the relapsed disease setting. Maintenance therapy with the PARP inhibitor, olaparib, plus antiangiogenic therapy offered a significant PFS benefit versus the antiangiogenic alone in women with newly diagnosed advanced ovarian cancer who tested positive for homologous recombination deficiency. Combination therapy was tolerated, with no new safety signals reported compared with monotherapy trials. PARP inhibitors and antiangiogenics have changed the landscape of ovarian cancer treatment. The PARP inhibitor plus antiangiogenic combination is a novel treatment option that appears promising in the first-line advanced and recurrent ovarian cancer settings, although the role of this combination in recurrent disease requires further elucidation. Defining which patients are candidates for monotherapy or combination therapy is critical, taking into consideration safety profiles of therapies alone or in combination, and how these treatments should be sequenced in clinical practice.
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Affiliation(s)
- Angeles Alvarez Secord
- Division of Gynecology Oncology, Department of Obstetrics and Gynecology, Duke Cancer Institute, Duke University Medical Center, Durham, NC, United States.
| | - David M O'Malley
- Division of Gynecology Oncology, The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, Columbus, OH, United States
| | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Shannon N Westin
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Joyce F Liu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
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19
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Zhou S, Zeng S, Shu Y. Drug-Drug Interactions at Organic Cation Transporter 1. Front Pharmacol 2021; 12:628705. [PMID: 33679412 PMCID: PMC7925875 DOI: 10.3389/fphar.2021.628705] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 01/13/2021] [Indexed: 12/19/2022] Open
Abstract
The interaction between drugs and various transporters is one of the decisive factors that affect the pharmacokinetics and pharmacodynamics of drugs. The organic cation transporter 1 (OCT1) is a member of the Solute Carrier 22A (SLC22A) family that plays a vital role in the membrane transport of organic cations including endogenous substances and xenobiotics. This article mainly discusses the drug-drug interactions (DDIs) mediated by OCT1 and their clinical significance.
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Affiliation(s)
- Shiwei Zhou
- Key Laboratory of Oral Medicine, School and Hospital of Stomatology, Guangzhou Medical University, Guangzhou, China.,Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Baltimore, MD, United States.,Department of Thyroid Surgery, The Second Xiangya Hospital, Central South University, Hunan, China
| | - Sujuan Zeng
- Key Laboratory of Oral Medicine, School and Hospital of Stomatology, Guangzhou Medical University, Guangzhou, China
| | - Yan Shu
- Key Laboratory of Oral Medicine, School and Hospital of Stomatology, Guangzhou Medical University, Guangzhou, China.,Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Baltimore, MD, United States
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20
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Wang L, Wang Q, Xu Y, Cui M, Han L. Advances in the Treatment of Ovarian Cancer Using PARP Inhibitors and the Underlying Mechanism of Resistance. Curr Drug Targets 2021; 21:167-178. [PMID: 31553293 DOI: 10.2174/1389450120666190925123507] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 08/27/2019] [Accepted: 09/02/2019] [Indexed: 12/15/2022]
Abstract
The standard treatment for advanced ovarian cancer is cytoreductive surgery followed by cytotoxic chemotherapy. However, it has high risk of recurrence and poor prognosis. Poly(ADPribose) polymerase (PARP) inhibitors selectively target DNA double-strand breaks (DSBs) in tumor cells that cannot be repaired and induce the synthetic lethality of BRCA1/2 mutation cancers. PARP inhibitors are clinically used to treat recurrent ovarian cancer and show significant efficacy in ovarian cancer patients with homologous recombination repair (HRR) pathway defects. PARP inhibitors also have significant clinical benefits in patients without HR defects. With the increasingly extensive clinical application of PARP inhibitors, the possibility of acquiring drug resistance is high. Therefore, clinical strategies should be adopted to manage drug resistance of PARP inhibitors. This study aims to summarize the indications and toxicity of PARP inhibitors, the mechanism of action, targeted treatment of drug resistance, and potential methods to manage drug-resistant diseases. We used the term "ovarian cancer" and the names of each PARP inhibitor as keywords to search articles published in the Medical Subject Headings (MeSH) on Pubmed, along with the keywords "clinicaltrials.gov" and "google.com/patents" as well as "uspto.gov." The FDA has approved olaparib, niraparib, and rucaparib for the treatment of recurrent epithelial ovarian cancer (EOC). Talazoparib and veliparib are currently in early trials and show promising clinical results. The mechanism underlying resistance to PARP inhibitors and the clinical strategies to overcome them remain unclear. Understanding the mechanism of resistance to PARP inhibitors and their relationship with platinum resistance may help with the development of antiresistance therapies and optimization of the sequence of drug application in the future clinical treatment of ovarian cancer.
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Affiliation(s)
- Ling Wang
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, China
| | - Qi Wang
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, China
| | - Yangchun Xu
- Department of Dermatology, The Second Hospital of Jilin University, Changchun, China
| | - Manhua Cui
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, China
| | - Liying Han
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, China
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21
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Li N, McInerny S, Zethoven M, Cheasley D, Lim BWX, Rowley SM, Devereux L, Grewal N, Ahmadloo S, Byrne D, Lee JEA, Li J, Fox SB, John T, Antill Y, Gorringe KL, James PA, Campbell IG. Combined Tumor Sequencing and Case-Control Analyses of RAD51C in Breast Cancer. J Natl Cancer Inst 2020; 111:1332-1338. [PMID: 30949688 DOI: 10.1093/jnci/djz045] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 02/07/2019] [Accepted: 04/03/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Loss-of-function variants in RAD51C are associated with familial ovarian cancer, but its role in hereditary breast cancer remains unclear. The aim of this study was to couple breast tumor sequencing with case-control data to clarify the contribution of RAD51C to hereditary breast cancer. METHODS RAD51C was sequenced in 3080 breast cancer index cases that were negative in BRCA1/2 clinical tests and 4840 population-matched cancer-free controls. Pedigree and pathology data were analyzed. Nine breast cancers and one ovarian cancer from RAD51C variant carriers were sequenced to identify biallelic inactivation of RAD51C, copy number variation, mutational signatures, and the spectrum of somatic mutations in breast cancer driver genes. The promoter of RAD51C was analyzed for DNA methylation. RESULTS A statistically significant excess of loss-of-function variants was identified in 3080 cases (0.4%) compared with 2 among 4840 controls (0.04%; odds ratio = 8.67, 95% confidence interval = 1.89 to 80.52, P< .001), with more than half of the carriers having no personal or family history of ovarian cancer. In addition, the association was highly statistically significant among cases with estrogen-negative (P <. 001) or triple-negative cancer (P < .001), but not in estrogen-positive cases. Tumor sequencing from carriers confirmed bi-allelic inactivation in all the triple-negative cases and was associated with high homologous recombination deficiency scores and mutational signature 3 indicating homologous recombination repair deficiency. CONCLUSIONS This study provides evidence that germline loss-of-function variants of RAD51C are associated with hereditary breast cancer, particularly triple-negative type. RAD51C-null breast cancers possess similar genomic and clinical features to BRCA1-null cancers and may also be vulnerable to DNA double-strand break inducing chemotherapies and poly ADP-ribose polymerase inhibitors.
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22
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Hennes ER, Dow-Hillgartner EN, Bergsbaken JJ, Piccolo JK. PARP-inhibitor potpourri: A comparative review of class safety, efficacy, and cost. J Oncol Pharm Pract 2020; 26:718-729. [DOI: 10.1177/1078155219895066] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Banerjee J, Lodhi N, Nguyen BN. The Role of Poly(ADP-Ribose) Polymerase-1 in Cutaneous Wound Healing. Adv Wound Care (New Rochelle) 2019; 8:634-643. [PMID: 31750014 DOI: 10.1089/wound.2018.0821] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Accepted: 03/13/2019] [Indexed: 12/15/2022] Open
Abstract
Critical Issue: Chronic nonhealing wounds of the lower extremities resulting in major amputations are a major health problem worldwide. Significance: Diabetes and ischemia are two major etiologies of nonhealing wounds of the lower extremities. Hyperglycemia from diabetes and oxidative stress from ischemia activate polyadenosine diphosphate (ADP)-ribose polymerase-1 (PARP-1), which is a nuclear enzyme that is best known for its role in DNA repair. However, the exact function of PARP-1 in ischemic/diabetic wound healing has not been well studied. Recent Advances: Poly-ADP-ribose (PAR) polymer has been detected in the wound bed and many of the PARylation-related reactions (oxidative stress response, expression of inflammatory cytokines and chemokines, cell proliferation, and migration) are important in the wound healing process. However, the role of PARP-1 in wound healing and the potential of targeting PARP-1 therapeutically in wounds are only recently being elucidated, with much still unknown. This review summarizes the recent advances in this field, highlighting some of the mechanisms through which PARP-1 may affect normal wound closure. Future Directions: The review also presents a perspective on some of the downstream targets of PARP-1 that may be explored for their role in wound healing and discusses about the therapeutic potential of PARP inhibitors for wound healing.
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Affiliation(s)
- Jaideep Banerjee
- Department of Vascular Surgery, George Washington University, Washington, District of Columbia
| | - Niraj Lodhi
- Department of Biomedical Research, Hackensack University Medical Center, Hackensack, New Jersey
| | - Bao-Ngoc Nguyen
- Department of Vascular Surgery, George Washington University, Washington, District of Columbia
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24
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Saad F, Shore N, Zhang T, Sharma S, Cho HK, Jacobs IA. Emerging therapeutic targets for patients with advanced prostate cancer. Cancer Treat Rev 2019; 76:1-9. [DOI: 10.1016/j.ctrv.2019.03.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 03/15/2019] [Accepted: 03/18/2019] [Indexed: 02/06/2023]
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25
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Gervasini G. Pharmacogenetics and personalized medicine. Are expectations being met? Med Clin (Barc) 2019; 152:368-371. [PMID: 30611536 DOI: 10.1016/j.medcli.2018.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 12/04/2018] [Accepted: 12/04/2018] [Indexed: 10/27/2022]
Affiliation(s)
- Guillermo Gervasini
- Departamento de Terapéutica Médico-Quirúrgica, Facultad de Medicina, Universidad de Extremadura, Badajoz, España.
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Poly (ADP-ribose) polymerase inhibitors combined with other small-molecular compounds for the treatment of ovarian cancer. Anticancer Drugs 2019; 30:554-561. [PMID: 30998513 DOI: 10.1097/cad.0000000000000793] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Ovarian cancer is a heterogeneous disease with complex molecular and genetic hallmarks. Benefitting from profound understanding of molecular mechanisms in ovarian cancer pathogenesis, novel targeted drugs have been actively explored in preclinical studies and clinical trials. Considered as one of the most potent and effective targeted therapies for the treatment of ovarian cancer, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) take advantages of synthetic lethality mechanisms to prevent DNA damage repair in cancer cells and cause their death, especially in cancers with BRCA mutations. Mounting evidence has indicated that the combination of PARPis with cytotoxic drugs or other targeted drugs has shown favorable synergistic effects. Excitingly, the antitumor activity of combination therapy of PARPis has been actively tested in multiple clinical trials and in-vitro or in-vivo experiments. In this review, we will briefly discuss the molecular mechanisms of PARPis combined with other therapeutic small-molecular compounds for the treatment of ovarian cancer.
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27
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Han Y, Chen MK, Wang HL, Hsu JL, Li CW, Chu YY, Liu CX, Nie L, Chan LC, Yam C, Wang SC, He GJ, Hortobagyi GN, Tan XD, Hung MC. Synergism of PARP inhibitor fluzoparib (HS10160) and MET inhibitor HS10241 in breast and ovarian cancer cells. Am J Cancer Res 2019; 9:608-618. [PMID: 30949414 PMCID: PMC6448061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 01/28/2019] [Indexed: 06/09/2023] Open
Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are promising targeted therapeutics for breast and ovarian cancers bearing a germline BRCA1/2 mutation (BRCA m), and several have already received regulatory approval in the United States. In patients with a BRCA m cancer, PARPi can increase the burden of unrepaired DNA double-strand breaks by blocking PARP activity and trapping PARP1 onto damaged DNA. Resistance to PARP inhibitors can block the formation of DNA double-strand breaks through BRCA-related DNA repair pathway. MET is a hyper-activated receptor tyrosine kinase expressed in multiple cancer types and the activation contributes to resistance to DNA damage-inducing therapeutic drugs. Our previous study showed that MET inhibition by pan-kinase inhibitors has synergism with PARPi in suppressing growth of breast cancer in vitro and in xenograft tumor models. In this study, we validated the inhibitory effect of novel inhibitors, HS10241 (selective MET inhibitor) and HS10160 (PARPi), to their target respectively in triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC) cells. We further demonstrated that these two inhibitors function synergistically in eliminating TNBC and HGSOC cells; combining with HS10241 increased DNA double-strand breaks induced by HS10160 in cancer cells; and PARP1 tyrosine (Y)-907 phosphorylation (PARP1 p-Y907) can be an effective biomarker as an indicator of MET-mediated PARPi in HGSOC. Our results suggest that the combination of HS10241 and HS10160 may benefit patients bearing tumors overexpressing MET as well as those resistant to single-agent PARPi treatment.
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Affiliation(s)
- Ye Han
- Department of Second Breast Surgery, China Medical University Affiliated Shengjing HospitalShenyang, P. R. China
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, TX, USA
| | - Mei-Kuang Chen
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, TX, USA
- Univeristy of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at HoustonHouston, TX 77030, USA
| | - Hung-Ling Wang
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical UniversityTaichung 40402, Taiwan
- Center for Molecular Medicine, China Medical University HospitalTaichung 40447, Taiwan
| | - Jennifer L Hsu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, TX, USA
| | - Chia-Wei Li
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, TX, USA
| | - Yu-Yi Chu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, TX, USA
| | - Chun-Xiao Liu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, TX, USA
| | - Lei Nie
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, TX, USA
| | - Li-Chuan Chan
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, TX, USA
- Univeristy of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at HoustonHouston, TX 77030, USA
| | - Clinton Yam
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, TX, USA
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer CenterHouston, TX, USA
- Univeristy of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at HoustonHouston, TX 77030, USA
| | - Shao-Chun Wang
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical UniversityTaichung 40402, Taiwan
- Center for Molecular Medicine, China Medical University HospitalTaichung 40447, Taiwan
| | - Gui-Jin He
- Department of Second Breast Surgery, China Medical University Affiliated Shengjing HospitalShenyang, P. R. China
| | - Gabriel N Hortobagyi
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer CenterHouston, TX, USA
| | - Xiao-Dong Tan
- Department of Thyroid and Pancreatic Surgery, China Medical University Affiliated Shengjing HospitalShenyang, P. R. China
| | - Mien-Chie Hung
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer CenterHouston, TX, USA
- Univeristy of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at HoustonHouston, TX 77030, USA
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical UniversityTaichung 40402, Taiwan
- Center for Molecular Medicine, China Medical University HospitalTaichung 40447, Taiwan
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Baloch T, López-Ozuna VM, Wang Q, Matanis E, Kessous R, Kogan L, Yasmeen A, Gotlieb WH. Sequential therapeutic targeting of ovarian Cancer harboring dysfunctional BRCA1. BMC Cancer 2019; 19:44. [PMID: 30630446 PMCID: PMC6327434 DOI: 10.1186/s12885-018-5250-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Accepted: 12/26/2018] [Indexed: 12/19/2022] Open
Abstract
Background Poly (ADP-ribose) polymerase inhibitors (PARPi) have become the first targeted therapies available in the treatment of patients with high-grade serous ovarian cancer (HGSOC). We recently described a significant reduction in PARP1 protein levels in vitro and in vivo in patients treated with standard carboplatinum-paclitaxel chemotherapy, raising the question whether the sequence of treatment used today with chemotherapy followed by PARPi is optimal. In this study, we aim to evaluate if the sequence of PARPi followed by chemotherapy could be more beneficial. Methods BRCA1-mutated (UWB1.287, SNU-251), epigenetically-silenced (OVCAR8), and wild-type (SKOV3, A2780PAR & A2780CR) ovarian cancer cell lines were exposed to clinically relevant doses of PARPi followed by different doses of standard chemotherapy and compared to the inverse treatment. The therapeutic efficacy was assessed using colony formation assays. Flow cytometry was used to evaluate cell apoptosis rate and the changes in cell cycle. Finally, apoptotic and cell cycle protein expression was immunodetected using western blot. Results Exposure to PARPi prior to standard chemotherapy sensitized BRCA1-mutated or epigenetically-silenced BRCA1 cell lines to lower doses of chemotherapy. Similar results were observed in BRCA1 wild-type and cell lines in which BRCA1 functionality was restored. Moreover, this treatment increased the apoptotic rate in these cell lines. Conclusion Pre-treatment with PARPi followed by standard chemotherapy in vitro is more efficient in growth inhibition and induction of apoptosis compared to the administration of standard chemotherapy followed by PARPi. Electronic supplementary material The online version of this article (10.1186/s12885-018-5250-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Tahira Baloch
- Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, QC, Canada.,Department of Experimental Surgery, McGill University, Montreal, QC, Canada
| | - Vanessa M López-Ozuna
- Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, QC, Canada
| | - Qiong Wang
- Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, QC, Canada
| | - Emad Matanis
- Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, QC, Canada
| | - Roy Kessous
- Division of Gynecologic Oncology, Jewish General Hospital, McGill University, 3755 Cote Ste. Catherine Road, Montreal, QC, H3T 1E2, Canada.,Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, QC, Canada
| | - Liron Kogan
- Division of Gynecologic Oncology, Jewish General Hospital, McGill University, 3755 Cote Ste. Catherine Road, Montreal, QC, H3T 1E2, Canada.,Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, QC, Canada
| | - Amber Yasmeen
- Division of Gynecologic Oncology, Jewish General Hospital, McGill University, 3755 Cote Ste. Catherine Road, Montreal, QC, H3T 1E2, Canada. .,Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, QC, Canada.
| | - Walter H Gotlieb
- Division of Gynecologic Oncology, Jewish General Hospital, McGill University, 3755 Cote Ste. Catherine Road, Montreal, QC, H3T 1E2, Canada.,Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, QC, Canada.,Department of Experimental Medicine, McGill University, Montreal, QC, Canada
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