Abstract 3046: Combination therapy targeting genomic and signal transduction vulnerabilities in epithelioid hemangioendothelioma

Abstract Background: Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma that frequently presents with early onset metastasis and lacks an effective medical therapy. EHE sarcomas are defined by the presence of gene fusions, where 85-90% of all EHE tumors contain TAZ-CAMTA1 and 10-15% contain YAP-TFE3. These fusion proteins bypass regulation by the Hippo pathway and act as important transcriptional coactivators by activating a TEAD-based transcriptional program, which is responsible for activating genes in several downstream pathways, including the PI3K pathway. Topoisomerase II, a chromatin modifier, was found to act as a key cofactor for the TAZ-CAMTA1 and YAP-TFE3 transcriptional programs. Herein, we propose utilizing inhibitors as a combination therapy targeting the PI3K-Akt axis, topoisomerase II, and TEAD binding of the TAZ-CAMTA1 and YAP-TFE3 transcription factors. Methods: Experiments were completed utilizing NIH 3T3 cells or a human liposarcoma cell line, SW872, that have been engineered to express the TAZ-CAMTA1 or YAP-TFE3 fusion proteins, or human EHE extended primary cell cultures. Several in vitro hallmarks of cancer assays were performed including 3D soft agar or poly-HEMA assays to measure anchorage independent growth and 2D clonogenic assays to measure cell survival. In each assay, cells were treated with various concentrations of vehicle control, everolimus, an mTORC1 inhibitor, IK930/VT-107, TEAD inhibitors, teniposide, a topoisomerase II inhibitor, or a combination of two or all three. Results: In the cells mentioned above, treatment with everolimus, IK930, teniposide and the combination of everolimus and IK930 and teniposide and IK930 showed a dose dependent decrease in anchorage independent growth when compared to the vehicle control. In soft agar and poly-HEMA, synergy was found with the combination of everolimus and IK930 and teniposide and IK930. To examine the cytotoxicity of the drugs, a clonogenic assay was performed on cells treated with everolimus and IK930 and observed no apparent cytotoxicity in cells treated with these inhibitors, however we did see cytotoxicity when EHE cells were treated with VT-107. Discussion/Conclusion: Because most EHE cells contain either the TAZ-CAMTA1 or YAP-TFE3 fusion proteins that activate a transcriptome that promotes several hallmarks of cancer, targeting the main way the fusions interact with DNA could mitigate these effects. Previous studies investigating the use of monotherapies to target cells expressing the fusion proteins show limited effectiveness. However, targeting both the interaction of the fusion proteins’ ability to interact with DNA as well as an important pathway for EHE cells, such as the PI3K pathway, could lead to a greater effectiveness in decreasing EHE tumor progression. These studies here show everolimus, teniposide and IK930/VT-107 as a potential combination therapy for EHE. Citation Format: Gillian DeWane, Nicholas Scalora, Yuliia Drebot, Ali Khan, Souradip Sinha, Krishnendu Ghosh, Nicole Merritt, Colleen Fullenkamp, Munir Tanas. Combination therapy targeting genomic and signal transduction vulnerabilities in epithelioid hemangioendothelioma [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 3046.