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ARID1A, an epigenetic tumor suppressor, is the most common gene mutation in clear-cell ovarian cancers (CCOCs). CCOCs are often resistant to standard chemotherapy and lack effective therapies. We hypothesized that ARID1A loss would increase CCOC cell dependency on chromatin remodeling and DNA repair pathways for survival. We demonstrate that combining BRD4 inhibitor (BRD4i) with DNA damage response inhibitors (ATR or WEE1 inhibitors; e.g. BRD4i-ATRi) was synergistic at low doses leading to decreased survival, and colony formation in CCOC in an ARID1A dependent manner. BRD4i-ATRi caused significant tumor regression and increased overall survival in ARID1AMUT but not ARID1AWT patient-derived xenografts. Combination BRD4i-ATRi significantly increased γH2AX, and decreased RAD51 foci and BRCA1 expression, suggesting decreased ability to repair DNA double-strand-breaks (DSBs) by homologous-recombination in ARID1AMUT cells, and these effects were greater than monotherapies. These studies demonstrate BRD4i-ATRi is an effective treatment strategy that capitalizes on synthetic lethality with ARID1A loss in CCOC.
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OBJECTIVE: The aim of this study was to evaluate the efficacy of adding bevacizumab to paclitaxel and carboplatin and as maintenance in a larger cohort of patients with advanced or recurrent endometrial carcinoma. METHODS: We retrospectively identified endometrial cancer patients treated with paclitaxel (175 mg/m per 3 hours), carboplatin (area under the curve, 5) and bevacizumab (15 mg/kg) and maintenance bevacizumab treated in a post-protocol treatment cohort and evaluated them with our previously published phase 2 trial of this regimen. RESULTS: Twenty-seven additional patients were identified; 19 received the regimen as first-line therapy, and 8 received the regimen as second-line therapy after prior paclitaxel and carboplatin. The 19 patients who received first-line therapy were analyzed alone and with the 15 patients enrolled on protocol. The 2 cohorts were similar with respect to risk factors. Overall survival curves were not statistically different between the protocol and the postprotocol patients (log-rank test; P > 0.1). Collectively, a total of 266 courses (median, 6 courses; range, 1-20 courses) of carboplatin, paclitaxel, and bevacizumab combination therapy and 305 courses (median, 16 courses; range, 0-45courses) of bevacizumab maintenance therapy were administered as first-line therapy. Collectively, the median progression-free survival was 20 months, and median overall survival was 56 months. Among 29 patients with measurable disease, the response rate was 82.8% (95% confidence interval, 69.0%-96.5%; 15 complete responses and 9 partial responses). Among the 8 patients who received paclitaxel and carboplatin and bevacizumab as second-line therapy after paclitaxel and carboplatin, the response rate was 87.5% (6 complete responses, 1 partial response). Their median progression-free survival and median overall survival were not reached after a median follow-up of 23.5 months. CONCLUSIONS: Although there are inherent limitations to small retrospective studies, this second analysis confirms the high response rate, progression-free survival, and overall survival in the bevacizumab, paclitaxel, and carboplatin regimen as first-line therapy in advanced and recurrent endometrial carcinoma.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Endometriales/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Bevacizumab/administración & dosificación , Carboplatino/administración & dosificación , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Estudios RetrospectivosRESUMEN
Purpose: PARP inhibition (PARPi) has modest clinical activity in recurrent BRCA-mutant (BRCAMUT) high-grade serous ovarian cancers (HGSOC). We hypothesized that PARPi increases dependence on ATR/CHK1 such that combination PARPi with ATR/CHK1 blockade results in increased cell death and tumor regression.Experimental Design: Effects of PARPi (olaparib), CHK1 inhibition (CHK1i;MK8776), or ATR inhibition (ATRi;AZD6738) alone or in combination on survival, colony formation, cell cycle, genome instability, and apoptosis were evaluated in BRCA1/2MUT HGSOC cells. Tumor growth in vivo was evaluated using a BRCA2MUT patient-derived xenograft (PDX) model.Results: PARPi monotherapy resulted in a decrease in BRCAMUT cell survival, colony formation and suppressed but did not eliminate tumor growth at the maximum tolerated dose (MTD) in a BRCA2MUT PDX. PARPi treatment increased pATR and pCHK1, indicating activation of the ATR-CHK1 fork protection pathway is relied upon for genome stability under PARPi. Indeed, combination of ATRi or CHK1i with PARPi synergistically decreased survival and colony formation compared with single-agent treatments in BRCAMUT cells. Notably, PARPi led to G2 phase accumulation, and the addition of ATRi or CHK1i released cells from G2 causing premature mitotic entry with increased chromosomal aberrations and apoptosis. Moreover, the combinations of PARPi with ATRi or CHK1i were synergistic in causing tumor suppression in a BRCA2MUT PDX with the PARPi-ATRi combination inducing tumor regression and in most cases, complete remission.Conclusions: PARPi causes increased reliance on ATR/CHK1 for genome stability, and combination PARPi with ATR/CHK1i is more effective than PARPi alone in reducing tumor burden in BRCAMUT models. Clin Cancer Res; 23(12); 3097-108. ©2016 AACR.