LAUSR

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 calculate IC50 values. DSRCTs were more sensitive to Darolutamide than Enzalutamide, two different AR inhibitors. Dual targeting PI3K and mTOR with Gedatolisib was more effective than Alpelisib or Temsirolimus alone. Taking lessons learned from prostate cancer, we studied combination assays of AR antagonists combined with PI3K/mTOR inhibitors. Those assays suggested that Darolutamide and Gedatolisib effects were mainly additive, with a slight synergy. We conclude that DSRCT cell lines are responsive to AR blocking and highly sensitive to PI3K/mTOR inhibitors. A co-targeting strategy that jointly inhibits the AR and PI3K/mTOR pathways is being investigated in murine models and might be considered for future studies if the regimens have non-overlapping toxicity profiles. Roberto Cardenas-Zuniga, Asmaa G. Ahmed, Kien Ryan Cao, Abid Raza, Clement Agyemang, Danh Truong, Joseph Ludwig. Co-targeting AR, mTOR, and PI3K inhibitors in DSRCT as a novel therapeutic approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7036.