Abstract 7036: Co-targeting AR, mTOR, and PI3K inhibitors in DSRCT as a novel therapeutic approach

作者：Roberto Cárdenas-Zúñiga, Asmaa Ahmed, Kerun Cao, Ali Raza, Clement Agyemang, Danh D. Truong, Joseph A. Ludwig · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/1538-7445.am2025-7036 · 研究领域：Colorectal Cancer Treatments and Studies、Cancer Treatment and Pharmacology、Advanced Breast Cancer Therapies

Abstract DSRCT (Desmoplastic Small Round Cell Tumor) is a rare soft tissue sarcoma that appears in the abdominal and pelvic area of mainly young males. There is little information about the molecular mechanisms involved in its pathology. Despite existing treatment options such as surgery, chemotherapy, and radiation, the NIH estimates that the five-year survival rate is only 15%, with frequent recurrence. Thus, new molecular targets and more effective therapeutic strategies are needed. Due to the high prevalence in males during puberty and the fact that AR (Androgen Receptor) is expressed in DSRCT, we hypothesized that AR plays an essential role in DSRCT development. We evaluated sensitivity to DHT (Dihydrotestosterone) and its effect on proliferation in the presence of different FBS (Fetal Bovine Serum) concentrations. For this approach, the LNCaP (prostate cancer) cell line was used as control. Our results indicated that DSRCTs responded differently to DHT at different FBS concentrations. We observed that DHT stimulates AR phosphorylation and increases total AR, pS6, and total S6 protein levels. Next, we explored the sensitivity of DSRCT cell lines to Enzalutamide and Darolutamide inhibitors; Temsirolimus (an mTOR inhibitor); Alpelisib (a PI3K inhibitor); and Gedatolisib (a dual mTOR and pan-PI3K inhibitor). Individual drug sensitivity was evaluated using in vitro exposure via the classic dose-response curve assays, measuring viability with CellTiterGlo2.0 reagent to calcul...