PARP Inhibitors in Gynecologic Cancers: What Is the Next Big Development?

Lightfoot, Michelle D.S.; Montemorano, Lauren; Bixel, Kristin

doi:10.1007/s11912-020-0873-4

Cited by 18 publications

(23 citation statements)

References 49 publications

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“…There is a growing number of studies pointing out the potential benefit of PARPi treatment in other DDR genes deficiency outside BRCA mutations (e.g., ATM, ATR, BARD1, BRIP1, CHK1, CHK2, PALB2, RAD51 or FANC) or combination treatment with other chemotherapeutics and targeted therapy. For more information, the reader is referred to other excellent up to date reviews focused on PARP and its inhibitors [144][145][146][147][148]. However, in vitro and in vivo evidence suggest that mutations in PARP1 abolishing the DNA binding cause the resistance towards PARPi [149].…”

Section: Base Excision Repairmentioning

confidence: 99%

“…For instance, inhibition of PARP1 enzyme, a part of BER, results in persistent SSBs, the subsequent collapse of the replication fork, and the ultimate formation of DSBs. If this inhibition is applied in OvC tumors with defective HR, tumor cells utilize error-prone NHEJ, leading to the accumulation of DNA damage and cell death [144]. Since 2014, three PARPi have been approved by FDA and EMA for use in OvC-olaparib, rucaparib, and niraparib [144].…”

Section: Therapeutic Perspectives-targeting Of Dna Repair System In Omentioning

confidence: 99%

“…If this inhibition is applied in OvC tumors with defective HR, tumor cells utilize error-prone NHEJ, leading to the accumulation of DNA damage and cell death [144]. Since 2014, three PARPi have been approved by FDA and EMA for use in OvC-olaparib, rucaparib, and niraparib [144]. Another PARPi-veliparib and talazoparib-are showing promising clinical results and facing FDA and EMA approvals in the treatment of OvC shortly [193][194][195].…”

Section: Therapeutic Perspectives-targeting Of Dna Repair System In Omentioning

confidence: 99%

“…ATR inhibitor AZD6738 in combination with PARPi has revealed higher efficiency than PARPi alone [208,209]. Olaparib-approved by FDA and EMA for use in OvC therapy [144] Rucaparib-approved by FDA and EMA for use in OvC therapy [144] Niraparib-approved by FDA and EMA for use in OvC therapy [144] Veliparib-advanced clinical trials in combination with carboplatin and paclitaxel. Veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer PFS than carboplatin plus paclitaxel induction therapy alone [193,194] Talazoparib-ongoing advanced clinical trials [194,195] Cell cycle checkpoints…”

Section: Therapeutic Perspectives-targeting Of Dna Repair System In Omentioning

confidence: 99%

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DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

Tomášová

Čumová

Šeborová

et al. 2020

Cancers

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There is ample evidence for the essential involvement of DNA repair and DNA damage response in the onset of solid malignancies, including ovarian cancer. Indeed, high-penetrance germline mutations in DNA repair genes are important players in familial cancers: BRCA1, BRCA2 mutations or mismatch repair, and polymerase deficiency in colorectal, breast, and ovarian cancers. Recently, some molecular hallmarks (e.g., TP53, KRAS, BRAF, RAD51C/D or PTEN mutations) of ovarian carcinomas were identified. The manuscript overviews the role of DNA repair machinery in ovarian cancer, its risk, prognosis, and therapy outcome. We have attempted to expose molecular hallmarks of ovarian cancer with a focus on DNA repair system and scrutinized genetic, epigenetic, functional, and protein alterations in individual DNA repair pathways (homologous recombination, non-homologous end-joining, DNA mismatch repair, base- and nucleotide-excision repair, and direct repair). We suggest that lack of knowledge particularly in non-homologous end joining repair pathway and the interplay between DNA repair pathways needs to be confronted. The most important genes of the DNA repair system are emphasized and their targeting in ovarian cancer will deserve further attention. The function of those genes, as well as the functional status of the entire DNA repair pathways, should be investigated in detail in the near future.

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Section: Base Excision Repairmentioning

confidence: 99%

Section: Therapeutic Perspectives-targeting Of Dna Repair System In Omentioning

confidence: 99%

Section: Therapeutic Perspectives-targeting Of Dna Repair System In Omentioning

confidence: 99%

Section: Therapeutic Perspectives-targeting Of Dna Repair System In Omentioning

confidence: 99%

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DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

Tomášová

Čumová

Šeborová

et al. 2020

Cancers

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“…6 Underlying defects include genomic or somatic mutations of BRCA1 and BRCA2 genes or other genes involved in homologous recombination. 7 As a result, therapeutic opportunities may arise in HGSOC from targeting vulnerabilities stemming from the defective repair machinery, which have already been exploited with the clinical development and introduction of PARP (polyadenosine diphosphate ribose polymerase) inhibitors. Alternatively, recurrent amplifications of oncogenes that lead to increased expression and activity of their product proteins could provide targetable opportunities.…”

Section: Introductionmentioning

confidence: 99%

<p>Further Understanding of High-Grade Serous Ovarian Carcinogenesis: Potential Therapeutic Targets</p>

Voutsadakis¹

2020

CMAR

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High-grade serous ovarian carcinoma (HGSOC) is the most common type of ovarian cancer and the most lethal gynecologic malignancy due to advanced stage at presentation. Recent years have witnessed progress in the therapy of HGSOC with the introduction of PARP (poly-adenosine diphosphate ribose polymerase) inhibitors and the anti-angiogenic monoclonal antibody bevacizumab to the backbone of chemotherapy or as maintenance therapy after chemotherapy. The improved molecular understanding of ovarian cancer pathogenesis, which has brought these therapies into the clinic, aspires to extend the boundaries of therapies through elucidation of other molecular aspects of ovarian carcinogenesis. This accumulating knowledge has started to be translated to additional targeted therapies that are in various stages of development. These include inhibitors of the function of other proteins involved in homologous recombination deficiency (HRD), such as WEE1 kinase, ATM/ATR kinases and CDK12 inhibitors. Despite disappointing results with immune checkpoint inhibitors monotherapy, harnessing the immune system in HGSOC with combination therapies that promote antigen production and immune cell activation is an avenue being explored. This paper examines arising HGSOC therapies based on molecular understanding of pathogenesis.

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Prevalence and Landscape of Pathogenic or Likely Pathogenic Germline Variants and Their Association With Somatic Phenotype in Unselected Chinese Patients With Gynecologic Cancers

Wen

Sheng

et al. 2023

JAMA Netw Open

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ImportanceUnderstanding germline and somatic status in patients with gynecologic cancers could improve risk assessment and guide therapeutic decision-making.ObjectiveTo evaluate the prevalence and landscape of germline pathogenic or likely pathogenic (P/LP) variants and explore whether these variants are associated with somatic phenotypes and cancer risk in unselected patients with gynecologic cancers.Design, Setting, and ParticipantsThis cross-sectional study retrospectively enrolled unselected patients in China with a gynecologic cancer, including ovarian, cervical, and endometrial, who underwent tumor-normal sequencing using a 520-gene panel from October 1, 2017, through May 31, 2021.ExposureGermline variants in gynecologic cancers.Main Outcomes and MeasuresThe P/LP germline variant rates in 62 cancer predisposition genes were assessed using descriptive statistics. The associations of P/LP variant status with age, somatic profiles, and cancer risk were also investigated using the Fisher exact test or Student t test.ResultsA total of 1610 women (median [IQR] age, 54 [47-62] years; 1201 [74.6%] with stage III-IV disease) were included (945 with ovarian cancer, 307 with endometrial cancer, and 358 with cervical cancer). The prevalence of patients with P/LP variants was 20.5% (194 of 945) for ovarian cancer, 13.4% (41 of 307) for endometrial cancer, and 6.4% (23 of 358) for cervical cancer; 95.1% of the germline findings (n = 252) were potentially actionable, mainly in homologous recombination repair (HRR) and mismatch repair genes. Chinese patients with endometrial cancer had a higher rate of P/LP variants than a White population from The Cancer Genome Atlas (42 of 307 [13.7%] vs 24 of 367 [6.5%]; P = .003). In endometrial and cervical cancers, the prevalence of P/LP variants was 12.7% (30 of 237) and 4.8% (13 of 270), respectively, in patients diagnosed at age 45 years or older and increased to 25.0% (9 of 36; P = .09) and 12.0% (10 of 83; P = .04), respectively, for those with an onset age of less than 45 years. Mismatch repair P/LP variants were associated with a younger age at onset for ovarian cancer (46 vs 54 years; P = .02) and endometrial cancer (48 vs 57 years; P &lt; .001), while HRR P/LP variants were associated with a younger age at onset for cervical cancer (46 vs 52 years; P = .04). Carriers of HRR P/LP variants had more prevalent somatic TP53 variants and less common somatic variants in oncogenic driver genes vs noncarriers. BRCA1/2 P/LP variants were also associated with moderate risks for endometrial and cervical cancer.Conclusions and RelevanceThis study delineates the landscape of germline P/LP variants in Chinese women with gynecologic cancers. The findings highlight the hereditary factor in cervical cancer that has long been neglected and suggest the importance of next-generation sequencing–based genetic testing with a large gene panel for gynecologic cancers.

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PARP Inhibitors in Gynecologic Cancers: What Is the Next Big Development?

Cited by 18 publications

References 49 publications

DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

<p>Further Understanding of High-Grade Serous Ovarian Carcinogenesis: Potential Therapeutic Targets</p>

Prevalence and Landscape of Pathogenic or Likely Pathogenic Germline Variants and Their Association With Somatic Phenotype in Unselected Chinese Patients With Gynecologic Cancers

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