Abstract 5974: Novel combinational therapeutic strategy in angiosarcoma through PLK1 and mTOR co-inhibition

Abstract Angiosarcoma (AS) is a rare and highly aggressive vascular sarcoma characterized by a poor prognosis with a 5-year survival rate of only 20-30%. The underlying oncogenic drivers and potential therapeutic targets remain unidentified in most AS cases. Standard treatments, including chemotherapy, surgery, and radiotherapy, demonstrate limited efficacy and are frequently associated with relapse and metastatic progression. These challenges highlight an urgent need to identify novel therapeutic targets and develop effective strategies to improve outcomes for patients with angiosarcoma. We identified Polo-like kinase 1 (PLK1), an overexpressed mitotic kinase, as a potential therapeutic target in angiosarcoma (AS). PLK1, a key mitotic regulator, is a promising candidate for clinical intervention in AS. Through differential gene expression analysis in mouse and human AS models, combined with druggability assessments utilizing publicly available databases and AI-based tools, we have validated PLK1 as a promising therapeutic target for AS. Furthermore, our studies demonstrate the potential combinational synergy of PLK1 and mTOR inhibition using small molecule inhibitors. We have shown that genetic Plk1 depletion by doxycycline-inducible shRNAs and pharmacological PLK1 inhibition using small molecule inhibitor BI 6727 in AS cells reduces cell proliferation colony forming ability in vitro and demonstrates significantly reduced tumor growth in vivo. Moreover, our data reveal that genetic depletion of Plk1 delays tumor onset and significantly improves survival in genetically engineered angiosarcoma mouse models (GEMMs). Previously, we observed activation of the mTOR signaling pathway in AS GEMMs and demonstrated that AS cells are susceptible to mTOR inhibition. In the current study, we observed a synergistic combination of PLK1 inhibition by Volasertib and mTOR inhibition by Rapamycin in AS in vitro and in vivo. Our objective is to determine the mechanisms and pathways governing the development and progression of AS to generate novel precision-targeted therapies. Our findings conclude that PLK1 is a viable therapeutic target in AS, and the combined inhibition of PLK1 and mTOR represents a promising novel therapeutic strategy for this aggressive cancer. Citation Format: Nimod D. Janson, Alejandra R. Alzate, Annaleigh Powell-Benton, Bozhi Liu, Ant Murphy, Jason A. Hanna. Novel combinational therapeutic strategy in angiosarcoma through PLK1 and mTOR co-inhibition [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 5974.