# Project 1:  Identifying new therapeutic avenues to selectively target tumors with uncontrolled mTORC1 activation

> **NIH NIH P01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $484,846

## Abstract

Project Summary/Abstract
Project 1: Identifying new therapeutic avenues to selectivelytarget tumors with uncontrolled mTORC1
activ ation
While targeted cancer therapies offer great promise, the wiring and plasticity of oncogenic signaling networks
makes primary or acquired resistance virtually inevitable. Many of the most common oncogenes and tumor
suppressors underlying human cancers impinge on mTOR complex 1 (mTORC1) regulation as a shared
downstream target, resulting in aberrant activation of mTORC1 in over half of all cancers. Sustained mTORC1
signaling has emerged as a major mechanism of resistance to targeted cancer therapies. However, mTOR
inhibitors such as rapamycin have limited use on their own for inducing tumor regression. We hypothesize that
the inability of tumor cells to properly regulate mTORC1 signaling, which is known to promote a broad program
of anabolic metabolism, renders them more susceptible to inhibition of specific cellular pathways and
processes. We will use a combination of hypothesis-driven and unbiased approaches to identify the major
vulnerabilities stemming from uncontrolled mTORC1 activity. We take advantage of the high degree of
evolutionary conservation within the mTOR network and perform cross-species synthetic lethal (SL) screens
that initiate in Drosophila and end in mammalian tumor models to identify robust genetic relationships
selectively influencing tumor cell survival. The project integrates high-throughput screening technologies in
reductionist systems (Perrimon laboratory) with mechanistic characterization in cell and tumor models
(Manning laboratory). Within the broader context of this P01, the project is discovery-based and fundamental to
the overarching goal of understanding and targeting the signaling network that connects the hamartoma
syndrome tumor suppressors (TSC1, TSC2, PTEN, LKB1, and NF1). The novel candidate targets and
mechanisms revealed through our project will serve as a key point of integration for all 3 projects.

## Key facts

- **NIH application ID:** 10460140
- **Project number:** 5P01CA120964-15
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** David J. Kwiatkowski
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $484,846
- **Award type:** 5
- **Project period:** 2006-12-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10460140

## Citation

> US National Institutes of Health, RePORTER application 10460140, Project 1:  Identifying new therapeutic avenues to selectively target tumors with uncontrolled mTORC1 activation (5P01CA120964-15). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10460140. Licensed CC0.

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