# Project 2: Targeting the Hippo Pathway in Genetically Complex Sarcomas

> **NIH NIH P50** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $550,537

## Abstract

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.

## Key facts

- **NIH application ID:** 10848815
- **Project number:** 2P50CA217694-06A1
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** SAMUEL SINGER
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $550,537
- **Award type:** 2
- **Project period:** 2018-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848815

## Citation

> US National Institutes of Health, RePORTER application 10848815, Project 2: Targeting the Hippo Pathway in Genetically Complex Sarcomas (2P50CA217694-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10848815. Licensed CC0.

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