Olaparib In Ovarian Cancer Research Articles

CRABP2 reduces the sensitivity of Olaparib in ovarian cancer by downregulating Caspase-8 and decreasing the production of reactive oxygen species

Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, such as Olaparib, have been pivotal in treating BRCA-deficient ovarian cancer. However, their efficacy is limited in over 40% of BRCA-deficient patients, with acquired resistance posing new clinical challenges. To address this, we employed bioinformatics methods to identify key genes impacting Olaparib sensitivity in ovarian cancer. Through comprehensive analysis of public databases including GEO, CPTAC, Kaplan Meier Plotter, and CCLE, we identified CRABP2 as significantly upregulated at both mRNA and protein levels in ovarian cancer, correlating with poor prognosis and decreased Olaparib sensitivity. Using colony formation and CCK-8 assays, we confirmed that CRABP2 knockdown in OVCAR3 and TOV112D cells enhanced sensitivity to Olaparib. Additionally, 4D label-free quantitative proteomics analysis, GSEA, and GO/KEGG analysis revealed CRABP2's involvement in regulating oxidation signals. Flow cytometry, colony formation assays, and western blotting demonstrated that CRABP2 knockdown promoted ROS production by activating Caspase-8, thereby augmenting Olaparib sensitivity and inhibiting ovarian cancer cell proliferation. Moreover, in xenograft models, CRABP2 knockdown significantly suppressed tumorigenesis and enhanced Olaparib sensitivity, with the effect being reversed upon Caspase-8 knockdown. These findings suggest that CRABP2 may modulate Olaparib sensitivity in ovarian cancer through the Caspase-8/ROS axis, highlighting its potential as a target for Olaparib sensitization.

Tabersonine Enhances Olaparib Sensitivity through FHL1-Mediated Epithelial-Mesenchymal Transition in an Ovarian Tumor.

Ovarian cancer (OVC) is one of the most aggressive gynecological malignancies worldwide. Although olaparib treatment has shown favorable outcomes against the treatment of OVC, its effectiveness remains limited in some OVC patients. Investigating new strategies to improve the therapeutic efficacy of olaparib against OVC is imperative. Our study identified tabersonine, a natural indole alkaloid, for its potential to increase the chemosensitivity of olaparib in OVC. The combined treatment of olaparib and tabersonine synergistically inhibited cell proliferation in OVC cells and suppressed tumor growth in A2780 xenografts. The combined treatment effectively suppressed epithelial-mesenchymal transition (EMT) by altering the expression of E-cadherin, N-cadherin, and vimentin and induced DNA damage responses. Integrating quantitative proteomics, FHL1 was identified as a potential regulator to modulate EMT after tabersonine treatment. Increased expression of FHL1 was induced by tabersonine treatment, while downregulation of FHL1 reversed the inhibitory effects of tabersonine on OVC cells by mediating EMT. In vivo findings further reflected that the combined treatment of tabersonine and olaparib significantly inhibited tumor growth and OVC metastasis through upregulation of FHL1. Our findings reveal the role of tabersonine in improving the sensitivity of olaparib in OVC through FHL1-mediated EMT, suggesting that tabersonine holds promise for future application in OVC treatment.

Olaparib for ovarian cancer: a single-institution, multi-site qualitative study.

This qualitative study sought to learn patients' perspectives on olaparib - including maintenance olaparib - in their own words. Olaparib-treated patients were interviewed by phone. A semi-structured interview guide that focused on symptoms and quality of life was formulated in alignment with the study objective. Interviews were transcribed and analyzed with content analysis. Twenty olaparib-treated patients were interviewed. Four themes emerged: (1) The Long Cancer Journey. Patients prescribed olaparib appear to have had a long cancer journey, sometimes with prior cancer ("I had breast cancer in 1996") and sometimes with a long interval from an ovarian cancer diagnosis; (2) Adherence. Despite this journey, patients were adherent to olaparib ("I set it for an alarm 15min before I have to take [olaparib] and then exactly when I'm supposed to take it"); (3) Adherence Despite Challenges. Adherence continued despite side effects (although olaparib was "pretty tolerable"). This adherence also continued despite cost ("…for a month's supply, mine was $15,837… and my insurance covered some of it but not near enough"), and (4) Modifications in Perceptions of BRCA Status. Olaparib as cancer therapy influenced perceptions of BRCA mutations ("But I… I have to tell you, I'm grateful that I qualified to be on Lynparza®"). Although oral maintenance therapy for ovarian cancer is relatively new, patients appear willing to take olaparib long term; and they seem to take great lengths to remain adherent, despite having sometimes had a long cancer journey.

Abstract IA23: PI3K inhibitors as a backbone for combination treatments for breast and ovarian cancer

Abstract PI3K inhibitors reduce glucose uptake and utilization by tumors. Yet in solid tumor clinical trials the efficacy of PI3K -inhibitors as single agents has been limited. Therefore, we have focused on harnessing the antimetabolic efficacy of PI3K inhibitors to augment the efficacy of antineoplastic treatments. A recently completed clinical trial (NCT01623349) examined the combination of PI3Ki BYL719 and the PARPi olaparib in ovarian cancer (EOC). Of the 28 EOC patients, 10 (35.7%) had partial response (PR), 14 (50%) had stable disease (SD), 3 (10.7%) had progressive disease (PD), and 1 (3.6%) patient was unevaluable. ORR was 33.3% and 31.3% in platinum resistant/refractory gBRCAmut and gBRCAwt patients, respectively. These data show that combining BYL719 and olaparib is feasible with no unexpected toxicities and that the activity of olaparib/BYL719 in gBRCAwt platinum-resistant EOC appears significantly higher than expected compared to either olaparib or BYL719 monotherapies. Next-generation sequencing did not identify markers of responsiveness to this combination. To assess responsiveness to this combination functionally, we have developed novel methods to monitor the antimetabolic activity of PI3K inhibitors in vivo using functional MRI of tumors based on the interconversion of 13C-pyruvate to 13C-lactate as well as NMR spectroscopy of tumoral ATP stores. Citation Format: Gerburg Wulf, Panos Konstantinopoulos, William Barry, Olmo Sonzongi, Julia Eismann, Bose Kucherlapati, Ursula Matulonis. PI3K inhibitors as a backbone for combination treatments for breast and ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr IA23.

Abstract 4083: Crizotinib improves the therapeutic efficacy of olaparib in ovarian cancer

Abstract Despite improvements in treatment, ovarian cancer still proves lethal in >60% of cases. One of the most important factors contributing to poor patient outcomes is the ability of dormant ovarian cancer cells to survive following primary surgery and chemotherapy. Poly (ADP) ribose polymerase inhibitors (PARPi) are promising agents for treating both primary and recurrent ovarian cancers. However, acquired drug resistance to PARPi decreases the clinical efficacy of these agents. We have previously found that olaparib induces autophagy in ovarian cancer and the addition of drugs that inhibit autophagy, such as chloroquine, can overcome drug resistance and enhance the anti-cancer activity of PARP inhibitors in ovarian cancer cells, cell line-derived xenograft and patient-derived xenograft models. Building upon this work, our group has sought drugs that are selectively toxic for autophagic ovarian cancer cells and that might enhance sensitivity to PARP inhibitors. In a previous study, our laboratory had found that knockdown of the anaplastic lymphoma kinase (ALK) significantly reduced survival of ovarian cancer cells that were undergoing autophagy. The FDA-approved ALK inhibitor, crizotinib, exhibited significantly greater toxicity for autophagic ovarian cancer cells in culture and cured a fraction of mice with dormant, autophagic ovarian cancer xenografts. As olaparib induces autophagy in ovarian cancer cells and crizotinib selectively targets autophagic cancer cells, we 1) explored the vulnerability of autophagic cells to the combination treatment of olaparib and crizotinib both in vitro and in vivo; and 2) the mechanism by which the combination of olaparib and crizotinib regulates cell proliferation and programmed cell death. Enhancement of olaparib activity was observed in 4 ovarian cancer cell lines (OVCAR8, OVCAR3, HEY and SKOV3). Moreover, a combination of olaparib and crizotinib proved more effective than either single agent in a xenograft model of the OVCAR8 ovarian cancer cell line. Mechanistically, a combination of olaparib and crizotinib induces DNA damage and accumulation of γ-H2AX. A combination of olaparib and crizotinib increased reactive oxygen species, while decreasing the phosphorylation of AKT. This decrease in p-AKT was associated with a decrease in p-mTOR, all of which contributed to an increase in autophagy, documented by western blot analysis, LC3 puncta and electron microscopy. Decreased p-AKT also correlated with a decrease in its downstream effector, survivin, leading to apoptosis. Together, our data suggest that crizotinib can enhance the therapeutic efficacy of olaparib in ovarian cancer by modulating autophagy and apoptosis. Moreover, we have identified a unique combination of therapy with olaparib and crizotinib that could improve the therapeutic efficacy of olaparib and outcomes for ovarian cancer patients. Citation Format: Janice M. Santiago-O'Farrill, Alicia M. Blessing, Sarah E. Becker, Zhen Lu, Robert C. Bast. Crizotinib improves the therapeutic efficacy of olaparib in ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4083.

Olaparib in the treatment of ovarian cancer.

The poly ADP ribose polymerase olaparib is currently approved in front line BRCA-associated epithelial ovarian cancer (EOC), platinum-sensitive recurrence agnostic to BRCA status and for gBRCA as treatment in the fourth line and beyond. Women who are diagnosed with advanced stage EOC face a formidable challenge in overcoming their disease and achieving long-term, disease-free survival. The qualifier here is disease free. EOC is largely exquisitely chemosensitive, especially in the treatment naive (first line) setting and the expectation is that the vast majority of women will complete front line platinum-based chemotherapy with a response. When unselected (not selected by BRCA) women are enrolled on clinical trials, the response rate among those who have measurable disease at the time of chemotherapy initiation is 48% for carboplatin/paclitaxel and 67% for carboplatin/paclitaxel plus bevacizumab. When one considers the addition of women who start chemotherapy without measurable disease, they will likely also end chemotherapy without measurable disease and the overall rate of no evidence of disease at conclusion of chemotherapy approaches 80%. Despite this, the majority of women will suffer relapse of their disease, typically within the first 3 years following completion of therapy. Once recurrent, the disease is highly treatable for many years but no longer considered curable. This review will cover indications for olaparib in ovarian cancer as well as ongoing combination trials and rationale for these combinations.

Olaparib for the treatment of epithelial ovarian cancer

ABSTRACTIntroduction: Despite recent advances in the management of epithelial ovarian cancer, overall survival rates remain poor, and there is a pressing need to develop novel therapeutic agents and maintenance strategies to improve outcomes for women with this disease. Olaparib, a potent oral poly(ADP-ribose) polymerase (PARP) inhibitor, has demonstrated antitumor activity in women with ovarian cancer, associated with homologous recombination deficiency.Areas covered: This review outlines the rationale for PARP inhibitor therapy in ovarian cancer and summarizes the efficacy and tolerability data for olaparib to date. Ongoing phase III clinical trials of olaparib in ovarian cancer will be discussed.Expert opinion: There are a number of issues regarding the optimal use of olaparib in ovarian cancer, including the identification of a homologous recombination deficiency signature to predict treatment response, establishment of the optimal treatment setting (maintenance or relapsed disease), and evaluation of cost-effectiveness. Finally, the long term consequences of PARP inhibitors, including the risk of myelodysplasia and acute myeloid leukemia need to be quantified in ongoing large phase III clinical trials.

Emerging treatment options for recurrent ovarian cancer: the potential role of olaparib

Olaparib has shown promising anticancer activity as a single agent in the treatment and maintenance of recurrent ovarian cancer in early clinical trials, but it is far from standard therapy. This article outlines the problem of relapsed ovarian cancer and the mechanisms of poly(ADP-ribose) polymerase inhibitors and reviews the recent literature pertaining to olaparib in ovarian cancer.