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1.
N Engl J Med ; 381(20): 1929-1939, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31722153

RESUMO

BACKGROUND: Secondary surgical cytoreduction in women with platinum-sensitive, recurrent epithelial ovarian, primary peritoneal, or fallopian-tube ("ovarian") cancer is widely practiced but has not been evaluated in phase 3 investigation. METHODS: We randomly assigned patients with recurrent ovarian cancer who had received one previous therapy, had an interval during which no platinum-based chemotherapy was used (platinum-free interval) of 6 months or more, and had investigator-determined resectable disease (to no macroscopic residual disease) to undergo secondary surgical cytoreduction and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Adjuvant chemotherapy (paclitaxel-carboplatin or gemcitabine-carboplatin) and use of bevacizumab were at the discretion of the investigator. The primary end point was overall survival. RESULTS: A total of 485 patients underwent randomization, 240 to secondary cytoreduction before chemotherapy and 245 to chemotherapy alone. The median follow-up was 48.1 months. Complete gross resection was achieved in 67% of the patients assigned to surgery who underwent the procedure. Platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance was administered to 84% of the patients overall and was equally distributed between the two groups. The hazard ratio for death (surgery vs. no surgery) was 1.29 (95% confidence interval [CI], 0.97 to 1.72; P = 0.08), which corresponded to a median overall survival of 50.6 months and 64.7 months, respectively. Adjustment for platinum-free interval and chemotherapy choice did not alter the effect. The hazard ratio for disease progression or death (surgery vs. no surgery) was 0.82 (95% CI, 0.66 to 1.01; median progression-free survival, 18.9 months and 16.2 months, respectively). Surgical morbidity at 30 days was 9%; 1 patient (0.4%) died from postoperative complications. Patient-reported quality of life decreased significantly after surgery but did not differ significantly between the two groups after recovery. CONCLUSIONS: In this trial involving patients with platinum-sensitive, recurrent ovarian cancer, secondary surgical cytoreduction followed by chemotherapy did not result in longer overall survival than chemotherapy alone. (Funded by the National Cancer Institute and others; GOG-0213 ClinicalTrials.gov number, NCT00565851.).

2.
Int J Cancer ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714586

RESUMO

Endometrial cancers have high rates of phosphoinositide 3-kinase (PI3K) pathway alterations. MK-2206 is an allosteric inhibitor of AKT, an effector kinase of PI3K signals. We hypothesized patients with tumors harboring PIK3CA mutations would be more likely to benefit from MK-2206 than those without PIK3CA mutation. A phase II study was performed in patients with recurrent endometrial cancer; all histologies except carcinosarcoma were eligible. Up to 2 prior chemotherapy lines were permitted, excluding prior treatment with PI3K pathway inhibitors. The first 18 patients were treated with MK-2206 200mg weekly. Due to unacceptable toxicity, dose was reduced to 135mg. Co-primary endpoints were objective response rate (ORR) and progression free survival at 6 months (6moPFS). Thirty-seven patients were enrolled (1 ineligible). By somatic PIK3CA mutation analysis, 9 patients were mutant (MT) (1 with partial response [PR]/6moPFS, 2 with 6moPFS). Twenty-seven patients were wild-type (WT) (1 PR and 4 6moPFS). Most common toxicities were rash (44%), fatigue (41%), nausea (42%) and hyperglycemia (31%). Grade 3 and 4 toxicities occurred in 25% and 17% of patients, respectively. Exploratory analysis found serous histology had greater 6moPFS as compared to all other histologies (5/8 vs. 2/28, p=.003). PTEN expression was associated with median time to progression (p= 0.04). No other significant associations with PI3K pathway alterations were identified. There is limited single agent activity of MK-2206 in PIK3CA MT and PIK3CA WT endometrial cancer populations. Activity was detected in patients with serous histology and due to their poor outcomes warrants further study. (NCT01307631) This article is protected by copyright. All rights reserved.

3.
Gynecol Oncol ; 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31623857

RESUMO

OBJECTIVE: We sought to determine safety and efficacy of the AKT inhibitor, GSK2141795, combined with the MEK inhibitor, trametinib, in endometrial cancer. METHODS: Patients with measurable recurrent endometrial cancer were eligible. One to two prior cytotoxic regimens were allowed; prior use of a MEK or PI3K pathway inhibitor was excluded. Initial trial design consisted of a KRAS mutation stratified randomized phase II with a safety lead-in evaluating the combination. For the safety lead in, the previously recommended phase 2 dose (RP2D; trametinib 1.5 mg, GSK2141795 50 mg) was chosen for Dose Level 1 (DL1). RESULTS: Of 26 enrolled patients, 14 were treated on DL1 and 12 were treated on DL-1 (trametinib 1.5 mg, GSK2141795 25 mg). Most common histologies were endometrioid (58%) and serous (27%). Four of 25 (16%) patients were KRAS mutant. Dose limiting toxicities (DLTs) were assessed during cycle 1. DL1 had 8 DLTs (hypertension (n = 2), mucositis (2), rash (2), dehydration, stroke/acute kidney injury). DL1 was deemed non-tolerable so DL-1 was explored. DL-1 had no DLTs. Sixty-five percent of patients had ≥ grade 3 toxicity. There were no responses in DL1 (0%, 90%CI 0-15%) and 1 response in DL-1 (8.3%, 90%CI 0.4-33.9%). Proportion PFS at 6 months for DL1 is 14%, and 25% for DL-1. CONCLUSION: The combination of trametinib and GSK2141795 had high levels of toxicity in endometrial cancer at the previously RP2D but was tolerable at a reduced dose. Due to insufficient preliminary efficacy at a tolerable dose, the Phase II study was not initiated.

4.
Am J Obstet Gynecol ; 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31586602

RESUMO

BACKGROUND: Standard treatment of early cervical cancer involves a radical hysterectomy and retroperitoneal lymph node dissection. The existing evidence on the incidence of adverse events following minimally invasive versus open radical hysterectomy for early cervical cancer is either non-randomized or retrospective. OBJECTIVE: To compare the incidence of adverse events following minimally invasive versus open radical hysterectomy for early cervical cancer. STUDY DESIGN: The Laparoscopic Approach to Carcinoma of the Cervix (LACC) trial was a multinational, randomized non-inferiority trial conducted between 2008 and 2017, in which surgeons from 33 tertiary gynecological cancer centers in 24 countries randomized 631 women International Federation of Gynecology and Obstetrics 2009 stage IA1 with lymph-vascular invasion to IB1 cervical cancer to either minimally invasive versus open radical hysterectomy. Patients were randomly assigned to undergo minimally invasive (n = 319) or open radical hysterectomy (n = 312). The LACC trial was suspended for enrolment in September 2017 due to an increased risk of recurrence and death in the minimally invasive surgery group. Here we report on a secondary outcome measure, the incidence of intra and postoperative adverse events within 6 months after surgery. RESULTS: Of 631 patients randomized, 536 (85%) (mean age, 46.0 years) met inclusion criteria for this analysis; 279 (52%) underwent minimally invasive radical hysterectomy, and 257 (48%) underwent open radical hysterectomy. Of those, 300 (56%), 91 (16.9%), 69 (12.8%) experienced at least one grade 2+, grade 3+, or a serious adverse event. The incidence of intraoperative grade 2+ adverse events was 12% (34/279 patients) in the minimally invasive versus 10% (26/257) in the open group (p=0.45). The overall incidence of postoperative grade 2+ adverse events was 54% (152/279 patients) in the minimally invasive versus 48% (124/257) in the open group (p=0.14). CONCLUSIONS: For early cervical cancer, the use of minimally invasive compared with open radical hysterectomy resulted in a similar overall incidence of intraoperative or postoperative adverse events.

6.
Clin Cancer Res ; 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31628143

RESUMO

PURPOSE: Treatment for patients with recurrent endometrioid endometrial cancer (EEC) are limited as paclitaxel is the only second line chemotherapy with a response rate >13%. Targeting PIK3/mTOR in combination with hormonal therapy has shown promise. The addition of metformin may enhance this response. We conducted a phase II study evaluating everolimus, letrozole, and metformin in advanced/recurrent ECC. EXPERIMENTAL DESIGN: A Simon two-stage design was employed. Women with <2 prior chemotherapy regimens for recurrence were eligible. Pre-treatment biopsy was required, followed by everolimus 10mg PO, letrozole 2.5mg PO, and metformin 500mg PO BID on a 4 week cycle. The primary endpoint was clinical benefit (CB), defined as complete response (CR), partial response (PR), or stable disease (SD) confirmed at 16 weeks. Patients were treated until progression or toxicity. RESULTS: Sixty-two patients were enrolled. Median age was 62 years (40 - 77) with 401 cycles completed, median of 6 cycles (1 - 31). Fifty-four patients were evaluable for response with a CB rate of 50% (27/54). Best overall response (OR) was PR 28% (15/54) and SD 22% (12/54). Thirteen patients received > 12 cycles. Median follow-up was 17.9 months (2 - 47). Median PFS was 5.7 (95% CI 3.0 to 8.1) and OS was 19.6 months (95% CI 14.2 to 26.3). Positive progesterone receptor expression was associated with CB (89.5% versus 27.3%, p=0.001). CONCLUSIONS: Everolimus, letrozole and metformin resulted in 50% CB and 28% OR in women with recurrent EC. Progesterone receptor positive tumors may have better response; validation studies are needed.

7.
Cancer Biol Ther ; : 1-10, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640461

RESUMO

The objective of this study was to examine the clinical significance of EZH2 expression and the therapeutic efficacy of its silencing in endometrial cancer. EZH2 expression in clinical samples was evaluated using a tissue microarray and correlated with clinical outcomes. The biological roles of EZH2 were assayed in vitro and in vivo. Gene expression was examined to reveal the molecular mechanism underlying the roles of EZH2 in endometrial cancer. We found that EZH2 overexpression was significantly correlated with disease-free and overall survival of patients with endometrial cancer. EZH2 silencing resulted in decreased cell viability and invasiveness, and increased apoptosis. In addition, EZH2 silencing enhanced the cytotoxicity of taxanes and cisplatin in Hec-1A and Ishikawa endometrial cancer cells. EZH2 silencing using small-interfering RNA (siRNA) incorporated into chitosan nanoparticles (siRNA/CN) induced a significant anti-tumor effect compared with that observed in controls (66.6% reduction in Hec-1A cells and 63.2% reduction in Ishikawa cells, p < .05 for both). Moreover, EZH2 siRNA/CN in combination with taxanes produced more robust anti-tumor effects versus those induced by monotherapies (77.0% for Hec-1A cells and 57.7% for Ishikawa cells, p < .05 for both). These results were associated with decreased angiogenesis and cell proliferation, and enhanced apoptosis. Genomic analyses revealed that EZH2 silencing decreased the expression levels of many genes associated with tumor growth, including PRDX6. Collectively, these results support EZH2 as an attractive target for the therapeutic management of endometrial cancer.

8.
N Engl J Med ; 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31562800

RESUMO

BACKGROUND: Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma. METHODS: In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the veliparib-throughout group as compared with the control group, analyzed sequentially in the BRCA-mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the BRCA-mutation cohort), and the intention-to-treat population. RESULTS: A total of 1140 patients underwent randomization. In the BRCA-mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P<0.001); in the HRD cohort, it was 31.9 months and 20.5 months, respectively (hazard ratio, 0.57; 95 CI, 0.43 to 0.76; P<0.001); and in the intention-to-treat population, it was 23.5 months and 17.3 months (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). Veliparib led to a higher incidence of anemia and thrombocytopenia when combined with chemotherapy as well as of nausea and fatigue overall. CONCLUSIONS: Across all trial populations, a regimen of carboplatin, paclitaxel, and veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer progression-free survival than carboplatin plus paclitaxel induction therapy alone. The independent value of adding veliparib during induction therapy without veliparib maintenance was less clear. (Funded by AbbVie; VELIA/GOG-3005 ClinicalTrials.gov number, NCT02470585.).

9.
Oncology (Williston Park) ; 33(7)2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31365748

RESUMO

Angiogenesis is known to play an important role in normal ovarian physiology as well as in growth and progression of ovarian cancer. The first FDA approval of bevacizumab in 2004 was for metastatic colorectal cancer in combination with chemotherapy; this was a key point for several subsequent approvals of antiangiogenic drugs. The efficacy of bevacizumab treatment is modest, however, and most ovarian cancer patients eventually develop acquired resistance, which highlights the need for new targeted therapies and/or combination strategies. Understanding the multitude of variables in response to antiangiogenic therapy would offer potential strategies for selecting patients most likely to benefit from such therapy.

11.
Gynecol Oncol ; 155(1): 126-134, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31416612

RESUMO

OBJECTIVES: Our aim was to investigate the prevalence and potential risk factors for persistent and troublesome physical and psychological symptoms following treatment for ovarian cancer (OC). METHODS: OvQuest is an international, internet-based, cross-sectional questionnaire which explored symptom burden and quality of life (QOL) after treatment for OC. Eligible women were aged 18 and over, diagnosed with OC at least 6 months previously and had received chemotherapy. Self-report data were collected including demographics, diagnosis and treatment, and standardised instruments for treatment-related toxicities, QOL, physical activity (PA) and supportive care needs. RESULTS: The survey included 1360 patients, of whom 421 (31%) had been treated for recurrent OC. 78% reported symptoms of peripheral neuropathy, 60% significant fatigue, 48% mood disturbance and 59% moderate-severe insomnia. Rates of fatigue, mood disorders, neuropathy and insomnia did not differ between women with or without recurrence. The majority of respondents were overweight or obese (high BMI, 59%) and 35% reported low PA. Low PA and high BMI were associated with poorer QOL scores and higher symptom burden across a range of domains. CONCLUSION: Women living after a diagnosis of OC report a substantial and ongoing symptom burden which impacts significantly on their quality of life across multiple domains. The reported associations between obesity, physical inactivity and poor QOL warrant prospective evaluation of lifestyle interventions to improve QOL.


Assuntos
Sobreviventes de Câncer/psicologia , Neoplasias Ovarianas/psicologia , Adolescente , Adulto , Idoso , Estudos de Coortes , Estudos Transversais , Fadiga/etiologia , Fadiga/psicologia , Feminino , Humanos , Pessoa de Meia-Idade , Transtornos do Humor/etiologia , Transtornos do Humor/psicologia , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/psicologia , Recidiva Local de Neoplasia/terapia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/fisiopatologia , Neoplasias Ovarianas/terapia , Qualidade de Vida , Inquéritos e Questionários , Adulto Jovem
14.
Gynecol Oncol ; 154(3): 524-530, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31353053

RESUMO

OBJECTIVE: To determine the feasibility of pharmacologic beta-adrenergic blockade in women with newly diagnosed stage II-IV epithelial ovarian cancer (EOC) throughout primary treatment. METHODS: Patients initiated propranolol prior to beginning chemotherapy or surgery. Feasibility was assessed as proportion able to complete 6 chemotherapy cycles while on adrenergic suppression. Descriptive statistics summarized surveys, and paired changes were analyzed using signed rank tests. Random-intercept Tobit models examined immune response. RESULTS: Median age was 59.9; 88.5% were stage IIIC/IV; and 38.5% underwent primary debulking. Thirty-two patients were enrolled; 3 excluded because they never took propranolol; an additional 3 didn't meet inclusion criteria, leaving 26 evaluable. Eighteen of 26 (69%), 90% credible interval (CI) of 53-81%, completed 6 chemotherapy cycles plus propranolol (an 82% posterior probability that the true proportion of success is ≥60%). Among the 23 patients with baseline and six month follow up data, overall QOL, anxiety, and depression improved (P < 0.05) and leukocyte expression of pro-inflammatory genes declined (P = 0.03) after completion of therapy. Decrease from baseline of serum IL-6 and IL-8 preceded response to chemotherapy (P < 0.0014). Change from baseline IL-10 preceded complete response. CONCLUSION: Use of propranolol during primary treatment of EOC is feasible and treatment resulted in decrease in markers of adrenergic stress response. In combination with chemotherapy, propranolol potentially results in improved QOL over baseline.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Propranolol/administração & dosagem , Antagonistas Adrenérgicos beta/administração & dosagem , Idoso , Carboplatina/administração & dosagem , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/cirurgia , Quimioterapia Adjuvante , Citocinas/sangue , Citocinas/genética , Citocinas/imunologia , Estudos de Viabilidade , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Estudos Longitudinais , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/cirurgia , Paclitaxel/administração & dosagem , Projetos Piloto , Estudos Prospectivos , Qualidade de Vida
15.
J Clin Oncol ; 37(26): 2317-2328, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31216226

RESUMO

PURPOSE: We report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma. METHODS: A total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration v time curve 6) and paclitaxel (175 mg/m2) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for BRCA1/2 and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry. RESULTS: Median follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8 v 32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for BRCA1/2 mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non-BRCA1/2 HRR, the HR was 0.65 (95% CI, 0.51 to 0.85). BRCA1/2, HRR, and CD31 were not predictive of bevacizumab activity. CONCLUSION: No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for BRCA1/2 mutations and homologous recombination deficiency is essential.

16.
Clin Cancer Res ; 25(16): 4874-4880, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31126961

RESUMO

Gynecologic malignancies continue to be a major cause of morbidity and mortality in the United States despite recent advances in oncologic therapies. To realize the promise of immunotherapy and biomarker-driven approaches to improve clinical outcomes for patients, better communication among stakeholders in the drug development and approval pathways is needed. To this end, the FDA-AACR-SGO Drug Development in Gynecologic Malignancies Workshop brought together clinicians, patient advocates, researchers, industry representatives, and regulators in June 2018, to review the state of the science in gynecologic cancers and explore how scientific advances impact approval processes. Topics of discussion and key takeaways are summarized in this Perspectives in Regulatory Science and Policy article. Single-agent immunotherapies have demonstrated variable and often modest response rates among gynecologic cancers. Combination therapies and other novel approaches, such as cell-based therapies, may show improved efficacy compared with single-agent immunotherapies; however, utilizing innovative clinical trial designs will be necessary to progress further. Companion and complementary diagnostics inform physicians of potential benefits of specific therapeutics for patients; however, they serve different functions that have important regulatory implications, thus trialists should understand the distinctions between diagnostic types. PARP inhibitors hold great promise for treating ovarian cancers, both as monotherapies and in combination with chemotherapeutics, other targeted agents, and immunotherapies. Rare gynecologic cancers often exhibit unique molecular characteristics that can serve as effective targets to which novel therapeutics can be developed. This workshop highlighted the importance of future open discussions on scientific and regulatory challenges in drug development for gynecologic malignancies.

17.
Int J Gynecol Cancer ; 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118216

RESUMO

The use of poly(ADP-ribose) polymerase (PARP) inhibition is transforming care for the treatment of ovarian cancer, with three different PARP inhibitors (PARPi) gaining US Food and Drug Administration approval since 2014. Given the rapidly expanding use of PARPi, this review aims to summarize the key evidence for their use and therapeutic indications. Furthermore, we provide an overview of the development of PARPi resistance and the emerging role of PARPi combination therapies, including those with anti-angiogenic and immunotherapeutic agents.

19.
20.
Mol Cancer Ther ; 18(5): 969-979, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30926640

RESUMO

EP-100 is a synthetic lytic peptide that specifically targets the gonadotropin-releasing hormone receptor on cancer cells. To extend the utility of EP-100, we aimed to identify effective combination therapies with EP-100 for ovarian cancer and explore potential mechanisms of this combination. A series of in vitro (MTT assay, immunoblot analysis, reverse-phase protein array, comet assay, and immunofluorescence staining) and in vivo experiments were carried out to determine the biological effects of EP-100 alone and in combination with standard-of-care drugs. EP-100 decreased the viability of ovarian cancer cells and reduced tumor growth in orthotopic mouse models. Of five standard drugs tested (cisplatin, paclitaxel, doxorubicin, topotecan, and olaparib), we found that the combination of EP-100 and olaparib was synergistic in ovarian cancer cell lines. Further experiments revealed that combined treatment of EP-100 and olaparib significantly increased the number of nuclear foci of phosphorylated histone H2AX. In addition, the extent of DNA damage was significantly increased after treatment with EP-100 and olaparib in comet assay. We performed reverse-phase protein array analyses and identified that the PI3K/AKT pathway was inhibited by EP-100, which we validated with in vitro experiments. In vivo experiment using the HeyA8 mouse model demonstrated that mice treated with EP-100 and olaparib had lower tumor weights (0.06 ± 0.13 g) than those treated with a vehicle (1.19 ± 1.09 g), EP-100 alone (0.62 ± 0.78 g), or olaparib alone (0.50 ± 0.63 g). Our findings indicate that combining EP-100 with olaparib is a promising therapeutic strategy for ovarian cancer.

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