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Cervical cancer:a tale from HPV infection to parp inhibitors

Genes & Diseases 2023年第4期10卷 1445-1456页

作者： Minakshi Mann Vikram Pratap Singh Lalit Kumar Department of Medical Oncology Dr.B.R.A.Institute Rotary Cancer HospitalAll India Institute of Medical SciencesNew Delhi 110029India Department of Oncoanaesthesia and Palliative Medicine Dr.B.R.A.Institute Rotary Cancer HospitalAll India Institute of Medical SciencesNew Delhi 110029India Epigenetics Section Mouse Cancer Genetics ProgramCenter for Cancer ResearchNational Cancer InstituteFrederickMD 21702USA

Globally,cervical cancer(CxCa)ranks 4th common cancer among females and led to 569,847 incidences and 311,365 deaths in 2018.80%of CxCa cases occur due to persistent infection with a high-risk subtype of human papillomavirus(HPV-16 and 18).Smoking,high par-ity,and co-infection with type 2 herpes simplex or HIV are other known risk factors for *** histological subtypes are squamous(70%)and adenocarcinoma(25%).Presently,concur-rent radiation plus cisplatin(CDDP)-based chemotherapy is the standard treatment for CxCa ***,CDDP resistance and toxic side effects limit its efficacy,leading to a poorer response rate and an expected overall survival ranging from 10 to 17.5 *** drug uptake,increased DNA damage repair,increased CDDP inactivation,and overexpressed Bcl-2 or caspase inhibition,are primarily accountable mechanisms for CDDP resistance and improving CDDP’s efficacy remains the major ***(ADP-ribosyl)polymerase-1,an effective mediator of nucleotide excision repair pathway,is involved in DNA repair as well as maintaining genomic stability and is significantly expressed in malignant lymphomas,hepa-tocellular-,cervical-and colorectal carcinoma,which has been approved effective in mainte-nance therapy and may serve as an effective target to enhance CDDP sensitivity in ***,we summarize the etiology and epidemiology of and treatment for CxCa,the mechanism responsible for chemotherapy resistance,parp inhibitor as a possible therapy for CxCa,and other possible chemotherapeutic options for CxCa treatment.

关键词： Cervical cancer Chemotherapy Cisplatin Disease etiology and histology parp inhibitors Resistance

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Ovarian cancer recurrence:“is the definition of platinum resistance modified by parp inhibitors and other intervening treatments?”

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Cancer Drug Resistance 2022年第2期5卷 451-458页

作者： Tanja Pejovic Katherine Fitch Gordon Mills Knight Cancer Institute Oregon Health&Science UniversityPortlandOR 97239USA. Department of Obstetrics&Gynecology Oregon Health&Science UniversityPortlandOR 97239USA.

PolyADP ribose polymerase inhibitors(parpi)have transformed the treatment of ovarian *** in high-grade serous ovarian cancer(HGSOC),a disease characterized by homologous recombination deficiency(HRD),parpi have had a rapid and profound impact on the disease course,as well as biologic and biomarker definitions of HGSOC,thereby creating a paradigm shift in the approach to *** this review,we discuss the role of parpi in the maintenance treatment of HGSOC,its effect on platinum sensitivity,and cross-resistance between platinum and parp inhibitors.

关键词： parp inhibitors olaparib niraparib ovarian cancer maintenance therapy

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Deciphering resistancemechanisms and novel strategies to overcome drug resistance in ovarian cancer:a comprehensive review

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Oncology Research 2024年第5期32卷 831-847页

作者： EFFAT ALEMZADEH LEILA ALLAHQOLI AFROOZ MAZIDIMORADI ESMAT ALEMZADEH FAHIMEH GHASEMI HAMID SALEHINIYA IBRAHIM ALKATOUT Infectious Diseases Research Center Birjand University of Medical SciencesBirjandIran Department of Midwifery Ministry of Health and Medical EducationTehranIran Student Research Committee Shiraz University of Medical SciencesShirazIran Department of Biotechnology Faculty of MedicineBirjand University of Medical SciencesBirjandIran Cellular and Molecular Research Center Birjand University of Medical SciencesBirjandIran Social Determinants of Health Research Center Birjand University of Medical SciencesBirjandIran Kiel School of Gynaecological Endoscopy Campus KielUniversity Hospitals Schleswig-HolsteinKielGermany

Ovarian cancer is among the most lethal gynecological cancers,primarily due to the lack of specific symptoms leading to an advanced-stage diagnosis and resistance to *** resistance(DR)poses the most significant challenge in treating patients with existing *** Food and Drug Administration(FDA)has recently approved three new therapeutic drugs,including two poly(ADP-ribose)polymerase(parp)inhibitors(olaparib and niraparib)and one vascular endothelial growth factor(VEGF)inhibitor(bevacizumab)for maintenance ***,resistance to these new drugs has ***,understanding the mechanisms of DR and exploring new approaches to overcome them is crucial for effective *** this review,we summarize the major molecular mechanisms of DR and discuss novel strategies to combat DR.

关键词： Chemotherapy Drug resistance mechanisms Ovarian cancer parp inhibitors VEGF inhibitor

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mTORC2 promotes pancreatic cancer progression and parp inhibitor resistance

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Oncology Research 2023年第4期31卷 495-503页

作者： CHIWEN BU LIGANG ZHAO LISHAN WANG ZEQIAN YU JIAHUA ZHOU Department of Hepatobiliary and Pancreatic Surgery Zhongda HospitalSchool of MedicineSoutheast UniversityNanjing210009China School of Medicine Southeast UniversityNanjing210009China

Pancreatic cancer is one of the most aggressive cancers with a median survival time of less than 5 months,and conventional chemotherapeutics are the main treatment ***(ADP-ribose)polymerase(parp)inhibitors have been recently approved for BRCA1/2-mutant pancreatic cancer,opening a new era for targeted therapy for this ***,most pancreatic cancer patients carry wild-type BRCA1/2 with resistance to parp ***,we reported that mammalian target of rapamycin complex 2(mTORC2)kinase is overexpressed in pancreatic cancer tissues and promotes pancreatic cancer cell growth and ***,we found that knockdown of the mTORC2 obligate subunit Rictor sensitized pancreatic cancer cells to the parp inhibitor ***,we showed that mTORC2 positively regulates homologous recombination(HR)repair by modulating BRCA1 recruitment to DNA double-strand breaks(DSBs).In addition,we confirmed that combination treatment with the mTORC2 inhibitor PP242 and the parp inhibitor olaparib synergistically inhibited pancreatic cancer growth in ***,this study provides a novel target and strategy for optimizing parp inhibitor efficiency in pancreatic cancers.

关键词： mTORC2 Pancreatic cancer parp inhibitors HR repair DNA damage

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Targeting DNA repair for cancer treatment: Lessons from parp inhibitor trials

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Oncology Research 2023年第4期31卷 405-421页

作者： DHANYA K.NAMBIAR DEEPALI MISHRA RANA P.SINGH Department of Radiation Oncology Stanford University School of MedicineStanfordCA94305USA Cancer Biology Laboratory School of Life SciencesJawaharlal Nehru UniversityNew Delhi110067India Special Centre for Systems Medicine Jawaharlal Nehru UniversityNew Delhi10067India

Ionizing radiation is frequently used to treat solid tumors,as it causes DNA damage and kill cancer ***,damaged DNA is repaired involving poly-(ADP-ribose)polymerase-1(parp-1)causing resistance to radiation ***,parp-1 represents an important target in multiple cancer types,including prostate *** is a nuclear enzyme essential for single-strand DNA breaks *** parp-1 is lethal in a wide range of cancer cells that lack the homologous recombination repair(HR)*** article provides a concise and simplified overview of the development of parp inhibitors in the laboratory and their clinical *** focused on the use of parp inhibitors in various cancers,including prostate *** also discussed some of the underlying principles and challenges that may affect the clinical efficacy of parp inhibitors.

关键词： parp inhibitors Synthetic lethality DNA repair BRCA mutations

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Ovarian cancer recurrence:is the definition of platinum sensitivity modified by parpi,bevacizumab or other intervening treatments?:a clinical perspective

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Cancer Drug Resistance 2022年第2期5卷 415-423页

作者： Peter G.Rose Section of Gynecologic Oncology Women’s Health InstituteCleveland ClinicClevelandOhio 44195USA.

In view of the high risk of recurrent disease in stage III and IV ovarian cancer following primary first-line chemotherapy,a variety of maintenance and consolidation treatment strategies have been *** have included:radiation,intravenous or intraperitoneal chemotherapy,targeted therapies,and *** at this time is the use of Poly-adenosine ribose polymerase(parp)inhibitors and bevacizumab as maintenance *** effect these maintenance or consolidation therapies have on subsequent response to therapy,specifically platinum-based chemotherapy,is only beginning to be *** this manuscript,we review the impact of parp inhibitors and bevacizumab as well as radiation and maintenance chemotherapy on subsequent response to *** use of bevacizumab does not appear to adversely affect subsequent response to platinum-based chemotherapy or platinum-based chemotherapy with *** therapy with parp inhibitors induces platinum resistance to subsequent platinum-based therapy and negates classic predictors of response such as platinum-free interval and breast cancer susceptibility gene(BRCA)mutational status.

关键词： Maintenance consolidation parp inhibitors bevacizumab radiation chemotherapy

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The clinical challenges of homologous recombination proficiency in ovarian cancer: from intrinsic resistance to new treatment opportunities

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Cancer Drug Resistance 2023年第3期6卷 499-516页

作者： Teresa Zielli Intidhar Labidi-Galy Maria Del Grande Cristiana Sessa Ilaria Colombo Service of Medical Oncology Oncology Institute of Southern Switzerland(IOSI)EOCBellinzona 6500Switzerland Department of Oncology Geneva University HospitalsGeneva 1205Switzerland Department of Medicine Center of Translational Research in Onco-HematologyGeneva 1205Switzerland

Ovarian cancer is the most lethal gynecologic cancer. Optimal cytoreductive surgery followed by platinum-based chemotherapy with or without bevacizumab is the conventional therapeutic strategy. Since 2016, the pharmacological treatment of epithelial ovarian cancer has significantly changed following the introduction of the poly (ADP-ribose) polymerase inhibitors (parpi). BRCA1/2 mutations and homologous recombination deficiency (HRD) have been established as predictive biomarkers of the benefit from platinum-based chemotherapy and parpi. While in the absence of HRD (the so-called homologous recombination proficiency, HRp), patients derive minimal benefit from parpi, the use of the antiangiogenic agent bevacizumab in first line did not result in different efficacy according to the presence of homologous recombination repair (HRR) genes mutations. No clinical trials have currently compared parpi and bevacizumab as maintenance therapy in the HRp population. Different strategies are under investigation to overcome primary and acquired resistance to parpi and to increase the sensitivity of HRp tumors to these agents. These tumors are characterized by frequent amplifications of Cyclin E and MYC, resulting in high replication stress. Different agents targeting DNA replication stress, such as ATR, WEE1 and CHK1 inhibitors, are currently being explored in preclinical models and clinical trials and have shown promising preliminary signs of activity. In this review, we will summarize the available evidence on the activity of parpi in HRp tumors and the ongoing research to develop new treatment options in this hard-to-treat population.

关键词： parp inhibitors homologous recombination proficiency ovarian cancer parp inhibitor resistance replication stress

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Ovarian cancer recurrence:is the definition of platinum resistance modified by parpi and other intervening treatments?The evolving landscape in the management of platinum-resistant ovarian cancer

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Cancer Drug Resistance 2022年第2期5卷 424-435页

作者： Michael J.Flynn Jonathan A.Ledermann Department of Oncology University College London HospitalLondon NW12PGUnited Kingdom. UCL Cancer Institute University College LondonLondon WC1E 6DDUnited Kingdom.

Definitions of platinum resistance have been questioned and changed over the last five years,even though no predictive biomarker of resistance *** have sculpted how we approach platinum retreatment and,consequently,how we devise new treatment strategies for those patients with tumour progression on platinum ***-non-eligible ovarian cancer is treated with single-agent non-platinum *** bevacizumab can be added to chemotherapy,progression-free survival improves *** patients with a BRCA mutation,parp inhibitor monotherapy is an option compared to *** is currently no clearly identified role for immune-checkpoint inhibition in this patient *** review describes some of the challenges in treating patients with platinum resistance and suggests refinements in the selection of patients most likely to benefit from targeting a DNA damage response,angiogenesis or immune *** also describes novel agents of interest and possible mechanisms of the synergy of therapeutic combinations.

关键词： Platinum resistance parp inhibitors VEGF inhibitors immune checkpoint inhibitors DNA damage response

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Targeting the γH2AX-MDC1 interaction in parp inhibitor-based cancer therapy

Targeting the γH2AX-MDC1 interaction in PARP inhibitor-base...

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中国生物化学与分子生物学会2016年全国学术会议

作者： Xiuna Sun Yili Feng Tingjun Hou Xiehuang Sheng Xiujun Cai Anyong Xie Sir Run Run Shaw Hospital Zhejiang University Institute of Translational Medicine Zhejiang University College of Pharmaceutical Sciences Zhejiang University College of Chemistry Shandong Normal University

Homologous recombination(HR)is one of major mechanisms that repair DNA double strand breaks(DSBs)and helps maintain genome *** genes involved in HR contribute to hereditary and spontaneous cancer risk when *** particu... 详细信息

关键词： Homologous recombination parp inhibitors γH2AX-MDC1 interaction computer-aided virtual ligand screening small molecule compounds

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Inhibition of MUS81 improves the chemical sensitivity of olaparib by regulating MCM2 in epithelial ovarian cancer

Inhibition of MUS81 improves the chemical sensitivity of ola...

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2017年中国肿瘤标志物学术大会暨第十一届肿瘤标志物青年科学家论坛

作者：仲瑷玲张红琴卢仁泉郭林复旦大学附属肿瘤医院检验科

Purpose Dysfunction of the DNA repair pathway contributes to tumorigenesis and drug resistance. Methyl methanesulfonate and ultraviolet sensitive gene clone 81(MUS81), a key endonuclease in DNA repair, is generally considered a tumor suppressor;however, recent studies have revealed its tumor-promoting effect in epithelial ovarian cancer(EOC) and have shown that its over-expression is associated with cisplatin resistance. This study aimed to investigate the biological effects and mechanisms of MUS81-mediated activation of minichromosome maintenance complex component 2(MCM2) in response to chemotherapeutic drugs in vitro. Methods DNA damage was induced with UV and CPT treatment, and the interaction between MUS81 and MCM2 was confirmed by immunofluorescence and immunoprecipitation. MUS81 was downregulated by lentivirus-mediated RNAi in A2780 and SKOV3 cells. A qPCR-based homologous recombination(HR) assay kit was used to measure HR efficiency. The effect of MUS81 on cellular sensitivity to olaparib was investigated in cell proliferation and colony formation assays. Flow cytometry was used to determine the effects on biological processes such as cell cycle and apoptosis. Results The results showed that MUS81 interacts with MCM2 and participates in the DNA damage repair process. MUS81 modulated MCM2 levels and HR activity. Moreover, downregulation of MUS81 increased the sensitivity of EOC cells to olaparib by inducing S phase arrest and promoting apoptosis through the activation of MCM2. Conclusion These results suggest that MUS81 is a potential new target of olaparib for the treatment of EOC that may potently improve the chemosensitivity to parp inhibitors and provide a new approach for the future treatment of gynecological tumors.

关键词： MUS81 MCM2 Homologous recombination parp inhibitors EOC

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