Repurposing FDA approved drugs as radiosensitizers for treating hypoxic prostate cancer

Abstract Background The presence of hypoxia is a poor prognostic factor in prostate cancer and the hypoxic tumor microenvironment promotes radioresistance. There is potential for drug radiotherapy combinations to improve the therapeutic ratio. We aimed to investigate whether hypoxia-associated genes could be used to identify FDA approved drugs for repurposing for the treatment of hypoxic prostate cancer. Methods Hypoxia associated genes were identified and used in the connectivity mapping software QUADrATIC to identify FDA approved drugs as candidates for repurposing. Drugs identified were tested in vitro in prostate cancer cell lines (DU145, PC3, LNCAP). Cytotoxicity was investigated using the sulforhodamine B assay and radiosensitization using a clonogenic assay in normoxia and hypoxia. Results Menadione and gemcitabine had similar cytotoxicity in normoxia and hypoxia in all three cell lines. In DU145 cells, the radiation sensitizer enhancement ratio (SER) of menadione was 1.02 in normoxia and 1.15 in hypoxia. The SER of gemcitabine was 1.27 in normoxia and 1.09 in hypoxia. No radiosensitization was seen in PC3 cells. Conclusion Connectivity mapping can identify FDA approved drugs for potential repurposing that are linked to a radiobiologically relevant phenotype. Gemcitabine and menadione could be further investigated as potential radiosensitizers in prostate cancer

Focus, Vol. 1 No. 1

A literary magazine of student writing published by the Department of English of Stephen F. Austin State College.https://scholarworks.sfasu.edu/focus/1000/thumbnail.jp

Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherpy for ovarian carcinoma

Background: Chemotherapy with a platinum agent and a taxane (paclitaxel) is considered the standard of care for treatment of ovarian carcinoma. We compared the com-bination of docetaxel – carboplatin with the combination of paclitaxel – carboplatin as first-line chemotherapy for stage Ic–IV epithelial ovarian or primary peritoneal can-cer. Methods: We randomly assigned 1077 patients to receive docetaxel at 75 mg/m2 of body surface area (1-hour intravenous infusion) or paclitaxel at 175 mg/m2 (3-hour intravenous infusion). Both treatments then were followed by carboplatin to an area under the plasma concentration–time curve of 5. The treatments were re-peated every 3 weeks for six cycles; in responding pa-tients, an additional three cycles of single-agent carbopla-tin was permitted. Survival curves were calculated by the Kaplan–Meier method, and hazard ratios were estimated with the Cox proportional hazards model. All statistical tests were two-sided. Results: After a median follow-up of 23 months, both groups had similar progression-free sur-vival (medians of 15.0 months for docetaxel – carboplatin and 14.8 months for paclitaxel – carboplatin; hazard ratio [HR] docetaxel–paclitaxel 0.97, 95 % confidence inter-val [CI] 0.83 to 1.13; P .707), overall survival rates at 2 years (64.2 % and 68.9%, respectively; HR 1.13, 95% CI 0.92 to 1.39; P .238), and objective tumor (58.7

Baseline clinical predictors of antitumor response to the PARP inhibitor olaparib in germline BRCA1/2 mutated patients with advanced ovarian cancer.

BackgroundThe PARP inhibitor olaparib was recently granted Food and Drug Administration (FDA) accelerated approval in patients with advanced BRCA1/2 mutation ovarian cancer. However, antitumor responses are observed in only approximately 40% of patients and the impact of baseline clinical factors on response to treatment remains unclear. Although platinum sensitivity has been suggested as a marker of response to PARP inhibitors, patients with platinum-resistant disease still respond to olaparib.Results108 patients with advanced BRCA1/2 mutation ovarian cancers were included. The interval between the end of the most recent platinum chemotherapy and PARPi (PTPI) was used to predict response to olaparib independent of conventional definition of platinum sensitivity. RECIST complete response (CR) and partial response (PR) rates were 35% in patients with platinum-sensitive versus 13% in platinum-resistant (p<0.005). Independent of platinum sensitivity status, the RECIST CR/PR rates were 42% in patients with PTPI greater than 52 weeks and 18% in patients with PTPI less than 52 weeks (p=0.016). No association was found between baseline clinical factors such as FIGO staging, debulking surgery, BRCA1 versus BRCA2 mutations, prior history of breast cancer and prior chemotherapy for breast cancer, and the response to olaparib.MethodsWe conducted an international multicenter retrospective study to investigate the association between baseline clinical characteristics of patients with advanced BRCA1/2 mutation ovarian cancers from eight different cancer centers and their antitumor response to olaparib.ConclusionPTPI may be used to refine the prediction of response to PARP inhibition based on the conventional categorization of platinum sensitivity