RP2: Targeting Hippo Pathway Dependence in Genetically Complex Sarcomas ABSTRACT Our overall goal is to find effective targeted therapies for 4 of the most common and clinically aggressive histologic types of genetically complex sarcoma: well-differentiated liposarcoma (WDLS), dedifferentiated liposarcoma (DDLS), myxofibrosarcoma (MFS), and undifferentiated pleomorphic sarcoma (UPS). Disease recurrence after surgery and metastasis are common, and patients have few treatment options once they develop advanced disease. Therefore, new targeted therapies are urgently needed to improve patients' outcomes. However, the complexity of alterations in these sarcomas has made it difficult to find the true drivers of oncogenesis. Despite this complexity, we have found that all 4 subtypes appear to share critical dependence on activation of the Hippo pathway through increased expression of the transcriptional coactivators YAP and TAZ. Our preliminary results have further shown that WDLS, DDLS, MFS, and UPS rely on the RNA helicase eIF4A for the translation of the YAP, TAZ, and TEAD mRNAs into protein. We therefore hypothesize that most WDLS, DDLS, MFS, and UPS tumors depend on Hippo signaling and eIF4A for growth and survival. In this research project, we will first examine the role of the Hippo pathway in promoting sarcoma genesis, differentiation, progression, and metastasis. Second, we will evaluate the single-agent efficacy of the new eIF4A inhibitor TDI-7663 in genetically complex sarcoma models, both in cell lines and in a preclinical phase 2–like trial design using 182 patient-derived xenograft (PDX) models that capture the range of genotypes of these genetically complex sarcomas. The PDX trial will also allow a rigorous study of the mechanisms of es- cape from eIF4A inhibition by uncovering biomarkers of innate and acquired resistance through prolonged treatment with TDI-7663. We will map the effects of TDI-7663 on mRNA translation in relevant sarcoma cells and PDX models using ribosome footprinting. Finally, we seek to advance TDI-7663 toward the clinic through investigative new drug (IND)–enabling toxicity, pharmacology, and efficacy studies. Clarification of the roles of the Hippo pathway and oncogenic translation will elucidate mechanisms of tumorigenesis and metastasis, identify new drug targets, identify effective combination therapies to combat resistance, and enable precision oncology. We expect that the IND-enabling studies will lead to a phase 1 clinical trial of TDI-7663 in patients with DDLS, MFS, and UPS within 5 years.