scholarly journals Next generation sequencing identifies potential PARP inhibitor sensitive mutations

2021 ◽  
Vol 156 (Supplement_1) ◽  
pp. S135-S136
Author(s):  
R Humble ◽  
A Bossler
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Tumor Type ◽  
Cancer Mutation ◽  
Mutation Profile ◽  
Unknown Significance ◽  
Brca1 Brca2 ◽  
Tumor Types

Abstract Introduction/Objective Poly ADP-ribose polymerase (PARP) inhibitors are a novel and important drug class targeting homologous recombination DNA repair defects (HRD) and have been approved for use in breast, pancreatic and ovarian cancers. Originally targeted for loss of function mutations in BRCA1 and BRCA2, many other genes are involved in the HRD pathway; Rimar et al detailed 19 DNA repair genes associated with homologous recombination and PARP inhibitor sensitivity. Our 214 gene NGS panel, Iowa Cancer Mutation Profile, includes BRCA1, BRCA2 and 15 other HRD pathway genes. We reviewed cases from the prior 12 months to determine the frequency of HRD7 pathway gene variants in various tumor types with potential PARP inhibitor sensitivity. Methods/Case Report Iowa Cancer Mutation Profile NGS test results from June 4, 2020 through May 7, 2021 were reviewed for variants involving ATM, ATR, BAP1, BLM, BRCA1, BRCA2, CDK12, CHEK1, CHEK2, FANCA, FANCC, FANCD2, MRE11A, NBN, PALB2, RAD51c and RAD51d, categorized as pathogenic, likely pathogenic or of unknown significance and had the tumor type identified. Additional chart review for PARP inhibitor therapy was performed in cases of breast, pancreatic, and ovarian cancer. Results (if a Case Study enter NA) A total of 599 cases were reviewed with 234 found to have variants in genes with possible PARP inhibitor sensitivity. Of these 2% (n=8) and 11% (n=43) of variants were categorized as pathogenic or likely pathogenic while most (n=334) were categorized as variants of unknown significance. The pathogenic and likely pathogenic variants included mutations in ATM (n=13), BRCA2 (n=12), BAP1 (n=8), FANCA (n=5), BRCA1 (n=4), NBM (n=3), FANCD2 (n=2), ATR (n=1), CDK12 (n=1), FANCC (n=1), and RAD51d (n=1), and frameshift (n=19) and nonsense (n=19) alterations were most common. Non-small cell lung cancer was the most frequent tumor type identified (n=78). At this time no PARP inhibitors were identified for use in cases of breast (n=9), pancreatic (n=3) and ovarian cancer (n=33). Conclusion Review of our institutional results for mutations in HRD pathway genes identified possible PARP inhibitor sensitivity in 8% (46 of 599) of cases during the period of review in a wide variety of tumor types. Our results suggest that variants with possible sensitivity to PARP inhibitor therapy are frequently identified from many tumor types and should be a component of solid tumor mutation profiling.

scholarly journals PARP Inhibitors in Ovarian Cancer: The Route to “Ithaca”

Diagnostics ◽  
2019 ◽  
Vol 9 (2) ◽  
pp. 55 ◽  
Author(s):  
Boussios ◽  
Karathanasi ◽  
Cooke ◽  
Neille ◽  
Sadauskaite ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Current Evidence ◽  
Repair Pathway ◽  
Significant Efficacy

Poly (ADP-ribose) polymerase (PARP) inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Genomic instability characterizes high-grade serous ovarian cancer (HGSOC), with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Early studies have shown significant efficacy for PARP inhibitors in patients with germline breast related cancer antigens 1 and 2 (BRCA1/2) mutations. It has also become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this treatment. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The choice of which PARP inhibitor is mainly based upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of patients most likely to benefit from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The aim of this review is to describe the current evidence for PARP inhibitors in ovarian cancer, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolution of resistance.

scholarly journals The evolving role of PARP inhibitors in advanced ovarian cancer

2021 ◽  
Vol 12 (1) ◽  
pp. 82-104
Author(s):  
Sofia Levva ◽  
Aglaia Skolariki ◽  
Eleni Sogka ◽  
Alexandros Bokas ◽  
Avraam Assi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Parp Inhibitor ◽  
Advanced Ovarian Cancer ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Primary Analysis ◽  
Serious Adverse Events ◽  
Adverse Event Data ◽  
Inhibitor Resistance

Abstract The field of ovarian cancer has been revolutionized with the use of poly (ADP-ribose) polymerase (PARP) inhibitors, which present greater inhibition effect in epithelial subtype due to high rates of homologous recombination deficiency. PARP inhibition exploits this cancer pitfall by disrupting DNA repair, leading to genomic instability and apoptosis. Three PARP inhibitors (olaparib, niraparib, and rucaparib) are now approved for use in women with epithelial ovarian cancer, while others are under development. Among women with BRCA1/2 mutations, maintenance PARP therapy has led to a nearly fourfold prolongation of PFS, while those without BRCA1/2 mutations experience an approximately twofold increase in PFS. Differences in trial design, patient selection and primary analysis population affect the conclusions on PARP inhibitors. Limited OS data have been published and there is also limited experience regarding long-term safety. With regard to toxicity profile, there are no differences in serious adverse events between the experimental and control groups. However, combining adverse event data from maintenance phases, a trend towards more events in the experimental group, compared with controls, has been shown. The mechanisms of PARP-inhibitor resistance include restoration of HR through reversion mutations in HR genes, leading to resumed HR function. Other mechanisms that sustain sufficient DNA repair are discussed as well. PARP inhibitors play a pivotal role in the management of ovarian cancer, affecting the future treatment choices. Defining exactly which patients will benefit from them is a challenge and the need for HRD testing to define ‘BRCA-ness’ will add additional costs to treatment.

Rare BAP1 variant of unknown significance (VUS) and analysis of BAP1 codon 146 genomics: Potential germline and therapeutic implications.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10533-10533
Author(s):  
Jo-Ellen Murphy ◽  
Sara Sadan ◽  
Jessica Kim Lee ◽  
Jana Pruski-Clark ◽  
Rebecca Sutphen ◽  
...  
Keyword(s):  
Dna Repair ◽  
Parp Inhibitors ◽  
Unknown Primary ◽  
Cellular Functions ◽  
Therapeutic Implications ◽  
Unknown Significance ◽  
Tumor Mutational Burden ◽  
Tumor Types ◽  
Cancer Côlon

10533 Background: The BAP1 gene ( B RCA1-Associated Protein) encodes a protein ubiquitin carboxyl-terminal hydrolase (BAP1), which removes ubiquitin moieties and regulates various cellular functions including DNA repair. This association has driven interest in defining if BAP1 variants confer susceptibility to PARP inhibitors (PARPi). Germline and somatic BAP1 alterations are both rare, mostly unique, often classified as VUS’s, and associated with a broad range of overlapping tumor types. Based on the identification of a BAP1 R146K VUS variant in tumor, also previously identified as germline, an analysis of BAP1 codon 146 alterations was initiated to explore potential genetic and therapeutic implications. Methods: 394,756 tumor specimens were tested using hybrid capture-based genomic profiling (Foundation Medicine) for all variant types and Tumor Mutational Burden (TMB). BAP1 codon 146 cases were analyzed for clinicogenomic features and germline results when available. Results: BAP1 codon 146 variants were identified in 23 unique patients across the following tumor types: cholangiocarcinoma (CCA) (4), mesothelioma (4), NSCLC (3), RCC (2), ocular melanoma (2), and carcinoma of unknown primary (CUP) (3); many of which overlap with known and suspected germline associated BAP1 syndromic tumor types. BAP1 R146 mutations were classified as VUS in 16 patients and 7 were likely or known pathogenic. In 20 of the 23 cases where zygosity could be determined 16 (80%) were homozygous and 4 (20%) were heterozygous. In 2 of the 3 NSCLC cases, the BAP1 variant appeared likely somatic and/or associated with a high TMB. A previously reported germline BAP1 variant in a RCC patient, R146K, occurred 5 times in our tumor database. One case which was homozygous in tumor and confirmed in germline occurred in a patient who had both breast and CCA. She also had a sibling with RCC who shared the germline BAP1 R146K variant along with multiple 1st and 2nd degree relatives with RCC, mesothelioma, melanoma, liver cancer, colon cancer, and a cancer of unknown primary. Conclusions: Codon 146 of BAP1 localizes to the UCH (ubiquitin carboxyl hydrolase) domain, which includes the BARD1 interaction region. Loss of BAP1 activity as a consequence of germline or somatic mutation likely impacts ubiquitination status and activity of downstream proteins, such as those involved in DNA repair. For patients with suspected BAP1 inactivating alterations, often seen in non-homologous recombination deficiency related tumor types, PARPi therapy may be relevant. As demonstrated here, variants identified through tumor testing may also aid in re-classification of germline VUS’s. These results support the further investigation and validation of BAP1 alterations for germline risk stratification and therapeutic strategies with either PARPi and/or other therapies specific to tumors with impaired chromatin remodeling.

scholarly journals Combined Strategies with Poly (ADP-Ribose) Polymerase (PARP) Inhibitors for the Treatment of Ovarian Cancer: A Literature Review

Diagnostics ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 87 ◽  
Author(s):  
Stergios Boussios ◽  
Peeter Karihtala ◽  
Michele Moschetta ◽  
Afroditi Karathanasi ◽  
Agne Sadauskaite ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Advanced Ovarian Cancer ◽  
Pegylated Liposomal Doxorubicin ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Biologic Agent

Poly (ADP-ribose) polymerase (PARP) inhibitors are the first clinically approved drugs designed to exploit synthetic lethality, and were first introduced as a cancer-targeting strategy in 2005. They have led to a major change in the treatment of advanced ovarian cancer, and altered the natural history of a disease with extreme genetic complexity and defective DNA repair via homologous recombination (HR) pathway. Furthermore, additional mechanisms apart from breast related cancer antigens 1 and 2 (BRCA1/2) mutations can also result in HR pathway alterations and consequently lead to a clinical benefit from PARP inhibitors. Novel combinations of PARP inhibitors with other anticancer therapies are challenging, and better understanding of PARP biology, DNA repair mechanisms, and PARP inhibitor mechanisms of action is crucial. It seems that PARP inhibitor and biologic agent combinations appear well tolerated and clinically effective in both BRCA-mutated and wild-type cancers. They target differing aberrant and exploitable pathways in ovarian cancer, and may induce greater DNA damage and HR deficiency. The input of immunotherapy in ovarian cancer is based on the observation that immunosuppressive microenvironments can affect tumour growth, metastasis, and even treatment resistance. Several biologic agents have been studied in combination with PARP inhibitors, including inhibitors of vascular endothelial growth factor (VEGF; bevacizumab, cediranib), and PD-1 or PD-L1 (durvalumab, pembrolizumab, nivolumab), anti-CTLA4 monoclonal antibodies (tremelimumab), mTOR-(vistusertib), AKT-(capivasertib), and PI3K inhibitors (buparlisib, alpelisib), as well as MEK 1/2, and WEE1 inhibitors (selumetinib and adavosertib, respectively). Olaparib and veliparib have also been combined with chemotherapy with the rationale of disrupting base excision repair via PARP inhibition. Olaparib has been investigated with carboplatin and paclitaxel, whereas veliparib has been tested additionally in combination with temozolomide vs. pegylated liposomal doxorubicin, as well as with oral cyclophosphamide, and topoisomerase inhibitors. However, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations requires further investigation with dose escalation studies. In this review, we discuss multiple clinical trials that are underway examining the antitumor activity of such combination strategies.

scholarly journals Efficacy of PARP Inhibitors in the Treatment of Ovarian Cancer: A Literature-Based Review

2019 ◽  
Vol 05 (01) ◽  
pp. 01-18
Author(s):  
Vikas Goswami ◽  
Venkata Pradeep Babu Koyyala ◽  
Sumit Goyal ◽  
Manish Sharma ◽  
Varun Goel ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Germ Line ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Repair Mechanism ◽  
Selection Of

AbstractPoly (ADP-ribose) polymerase (PARP) inhibitors are a unique class of therapeutic agents that focus on tumors with deficiencies in the homologous recombination DNA repair mechanism. Genomic instability outlines high-grade serous ovarian cancer, with 50% of all tumors displaying defects in the important DNA repair mechanism of homologous recombination. Earlier research studies have demonstrated considerable efficiency for PARP inhibitors in patients with germ line breast-related cancer antigens 1 and 2 (BRCA-1/BRCA-2) mutations. It has also been observed that BRCA wild-type patients with other defects in the homologous recombination repair mechanism get benefited from this therapy. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The selection of PARP inhibitor is mainly dependent upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of cases which are most likely to get benefited from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The purpose of this review is to focus and describe the current evidences for PARP inhibitors in ovarian malignancy, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolving resistance.

scholarly journals Ovarian Cancer: Diagnostic Accuracy and Tumor Types Distribution in East Africa compared to North America

2020 ◽  
Author(s):  
Peter Fabian Rambau ◽  
Martin Köbel ◽  
Derek Tilley ◽  
Alex Mremi ◽  
Robert Lukande ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Diagnostic Accuracy ◽  
Ovarian Carcinoma ◽  
East Africa ◽  
Response To Therapy ◽  
Tumor Type ◽  
Integrated Diagnosis ◽  
Resource Limited ◽  
Haematoxylin And Eosin Stain ◽  
Tumor Types

Abstract Background Ovarian cancer is a spectrum of several histologically distinct tumor types which differ in etiology, response to therapy and prognosis. In a resource-limited settings, the diagnosis of ovarian cancer can be challenging. This study describes the distribution of ovarian cancer tumor types in East Africa as well as assessing the diagnostic accuracy by using contemporary methods. Methods Data from 210 women identified from the records with a diagnosis of ovarian cancer in a period of 15 years were included. Two tissue microarrays were constructed and stained with 20 antibodies relevant to ovarian cancer subtyping. An integrated diagnosis was reached by the review of full Haematoxylin and Eosin stained sections, with consideration of immunohistochemical results. The integrated diagnoses were compared with the original diagnoses, and the degree of agreement was evaluated by percentage and Kappa statistics. Results The estimated rates of ovarian cancer were much lower in East Africa compared to a North American population from Alberta, Canada. There was a higher proportion of sex cord stromal tumors and germ cell tumors in the East African population. Diagnostic accuracy for main ovarian tumor type categories was substantial (Kappa 0.70), but only fair for specific ovarian carcinoma histotypes (Kappa 0.34). Poor Haematoxylin and Eosin stain was the main factor hindering correct diagnosis, which was not related to tissue processing. Conclusions In a resource- limited setting, where immunohistochemistry is not routinely carried out, diagnostic accuracy for the main categories of ovarian carcinoma is substantial and could be further improved by standardization of the basic Haematoxylin and Eosin stain.

scholarly journals PARP Inhibitors in Prostate Cancer—The Preclinical Rationale and Current Clinical Development

Genes ◽  
2019 ◽  
Vol 10 (8) ◽  
pp. 565 ◽  
Author(s):  
Virtanen ◽  
Paunu ◽  
Ahlskog ◽  
Varnai ◽  
Sipeky ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Dna Repair ◽  
Therapeutic Potential ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Treatment Modalities ◽  
Cancer Type ◽  
Castration Resistance ◽  
Single Strand Break

Prostate cancer is globally the second most commonly diagnosed cancer type in men.Recent studies suggest that mutations in DNA repair genes are associated with aggressive forms ofprostate cancer and castration resistance. Prostate cancer with DNA repair defects may bevulnerable to therapeutic targeting by Poly(ADP‐ribose) polymerase (PARP) inhibitors. PARPenzymes modify target proteins with ADP‐ribose in a process called PARylation and are inparticular involved in single strand break repair. The rationale behind the clinical trials that led tothe current use of PARP inhibitors to treat cancer was to target the dependence of BRCA‐mutantcancer cells on the PARP‐associated repair pathway due to deficiency in homologousrecombination. However, recent studies have proposed therapeutic potential for PARP inhibitorsin tumors with a variety of vulnerabilities generating dependence on PARP beyond the syntheticlethal targeting of BRCA1/BRCA2 mutated tumors, suggesting a wider potential than initiallythought. Importantly, PARP‐associated DNA repair pathways are also closely connected toandrogen receptor (AR) signaling, which is a key regulator of tumor growth and a centraltherapeutic target in prostate cancer. In this review, we provide an extensive overview of publishedand ongoing trials exploring PARP inhibitors in treatment of prostate cancer and discuss theunderlying biology. Several clinical trials are currently studying PARP inhibitor mono‐andcombination therapies in the treatment of prostate cancer. Integration of drugs targeting DNArepair pathways in prostate cancer treatment modalities allows developing of more personalizedcare taking also into account the genetic makeup of individual tumors.

scholarly journals PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers

2019 ◽  
Vol 8 (4) ◽  
pp. 435 ◽  
Author(s):  
Man Keung ◽  
Yanyuan Wu ◽  
Jaydutt Vadgama
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Predictive Biomarkers ◽  
Parp Inhibitors ◽  
Homologous Recombination Deficiency ◽  
Repair Pathways

Poly (ADP-ribose) polymerases (PARPs) play an important role in various cellular processes, such as replication, recombination, chromatin remodeling, and DNA repair. Emphasizing PARP’s role in facilitating DNA repair, the PARP pathway has been a target for cancer researchers in developing compounds which selectively target cancer cells and increase sensitivity of cancer cells to other anticancer agents, but which also leave normal cells unaffected. Since certain tumors (BRCA1/2 mutants) have deficient homologous recombination repair pathways, they depend on PARP-mediated base excision repair for survival. Thus, inhibition of PARP is a promising strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Although PARP inhibitor therapy has predominantly targeted BRCA-mutated cancers, this review also highlights the growing conversation around PARP inhibitor treatment for non-BRCA-mutant tumors, those which exhibit BRCAness and homologous recombination deficiency. We provide an update on the field’s progress by considering PARP inhibitor mechanisms, predictive biomarkers, and clinical trials of PARP inhibitors in development. Bringing light to these findings would provide a basis for expanding the use of PARP inhibitors beyond BRCA-mutant breast tumors.

scholarly journals First-line PARP inhibitors in ovarian cancer: summary of an ESMO Open - Cancer Horizons round-table discussion

ESMO Open ◽  
2020 ◽  
Vol 5 (6) ◽  
pp. e001110
Author(s):  
Susana Banerjee ◽  
Antonio Gonzalez-Martin ◽  
Philipp Harter ◽  
Domenica Lorusso ◽  
Kathleen N Moore ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Therapy ◽  
Parp Inhibitor ◽  
Advanced Ovarian Cancer ◽  
Round Table ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
European Medicines Agency ◽  
First Line ◽  
Phase Iii Trials

Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the latest breakthrough in the management of newly diagnosed advanced ovarian cancer. The results of the SOLO-1 trial in 2018 led to European Medicines Agency and Food and Drug Administration approval of olaparib as first-line maintenance therapy in patients with BRCA1/2 mutation, establishing a new standard of care. Subsequently, the results of three phase III trials (PRIMA, PAOLA-1, VELIA) evaluating the use of first-line PARP inhibitors beyond patients with BRCA1/2 mutations and as combination strategies were presented in 2019, leading to the recent approval of maintenance niraparib irrespective of biomarker status and olaparib in combination with bevacizumab in homologous recombination deficiency-positive-associated advanced ovarian cancer. An ESMO Open - Cancer Horizons round-table expert panel discussed the four phase III trials of first-line PARP inhibitor therapy and how they are changing the clinical management of advanced ovarian cancer.

scholarly journals Genome-scale CRISPR knockout screen identifies TIGAR as a modifier of PARP inhibitor sensitivity

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Pingping Fang ◽  
Cristabelle De Souza ◽  
Kay Minn ◽  
Jeremy Chien
Keyword(s):  
Ovarian Cancer ◽  
Metabolic Pathways ◽  
Clinical Utility ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Loss Of Function ◽  
Poor Overall Survival ◽  
Cytotoxic Effects ◽  
Cancer Types ◽  
Genome Scale

Abstract Treatment of cancer with poly (ADP-ribose) polymerase (PARP) inhibitors is currently limited to cells defective in the homologous recombination (HR) pathway. Identification of genetic targets that induce or mimic HR deficiencies will extend the clinical utility of PARP inhibitors. Here we perform a CRISPR/Cas9-based genome-scale loss-of-function screen, using the sensitivity of PARP inhibitor olaparib as a surrogate. We identify C12orf5, encoding TP53 induced glycolysis and apoptosis regulator (TIGAR), as a modifier of PARP inhibitor response. We show that TIGAR is amplified in several cancer types, and higher expression of TIGAR associates with poor overall survival in ovarian cancer. TIGAR knockdown enhances sensitivity to olaparib in cancer cells via downregulation of BRCA1 and the Fanconi anemia pathway and increases senescence of these cells by affecting metabolic pathways and increasing the cytotoxic effects of olaparib. Our results indicate TIGAR should be explored as a therapeutic target for treating cancer and extending the use of PARP inhibitors.

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