# Targeting Oncogenic Pathways in Genetically Complex Sarcomas

> **NIH NIH P50** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $416,455

## Abstract

RP-3: Targeting oncogenic pathways in genetically complex sarcomas
ABSTRACT
Our overall goal is to find effective targeted therapies for two of the most common and aggressive types
of genetically complex sarcomas: myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma
(UPS). The development of new targeted therapies is urgent and vital for improving outcomes of these
patients. However, the complexity of alterations in these sarcomas has made it difficult to find the true
drivers of oncogenesis. We found that high expression of ITGA10 (integrin-α10) in MFS and UPS drives
sarcomagenesis by activating RAC/PAK and PI3K/mTOR signaling, and that 85% of MFS and UPS
harbor alterations that can activate the PI3K/mTOR signaling cascade. Signaling in this cascade
stimulates protein translation, and our preliminary results suggest that MFS and UPS, as well as
dedifferentiated liposarcoma (DDLS), rely on oncogenic translation enabled by the RNA helicase eIF4A.
We therefore hypothesize that most MFS/UPS will be dependent on PI3K/mTOR signaling and eIF4A
for growth and survival. First, we plan to define the role of the PI3K/mTOR and MAPK pathway
activation in sarcomagenesis and identify molecular alterations that associate with outcome. Second, we
plan to determine the efficacy of mTOR, PI3K, and MEK inhibitors in MFS/UPS cell lines, xenografts
and PDX models. In preliminary data the PI3K/mTOR inhibitors alone led to feedback upregulation of
the MAPK pathway, which could cause adaptive resistance to therapy. Therefore, we will test combining
each of the PI3K and mTOR inhibitors with a MEK inhibitor, to test whether the combination blocks the
adaptive response and leads to synergistic suppression of MFS/UPS. Third, we will determine the
efficacy and mechanism of action of a new eIF4A inhibitor, CR31B, in MFS, UPS, and DDLS cell lines and
xenografts. To discover which mRNAs require eIF4A for their translation in these cell lines, we will
perform ribosome footprinting on CR31B-treated cells. We expect that mTOR, PI3K, and eIF4A inhibitors
will be effective therapy in the majority of MFS and UPS. Clarification of the roles of the PI3K/mTOR
and oncogenic translation pathways will elucidate mechanisms of tumorigenesis and metastasis, identify
new drug targets, identify effective combination therapies, and enable precision oncology. We expect
that at least one of the treatment strategies investigated in this proposal will lead to clinical trials for
patients with MFS and UPS.

## Key facts

- **NIH application ID:** 10247699
- **Project number:** 5P50CA217694-04
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** SAMUEL SINGER
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $416,455
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247699

## Citation

> US National Institutes of Health, RePORTER application 10247699, Targeting Oncogenic Pathways in Genetically Complex Sarcomas (5P50CA217694-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10247699. Licensed CC0.

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