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

> **NIH NIH P01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $468,591

## Abstract

Project 1 – Abstract
While mTORC1 is activated in a growth factor-independent manner in most human cancers and is believed to
contribute to the uncontrolled anabolic growth of tumors, mTOR inhibitors such as rapamycin and its analogs
(rapalogs) have had limited clinical success as anti-tumor agents. Furthermore, even in settings in which
tumors respond favorably to rapalogs, such as with the genetic tumor syndrome tuberous sclerosis complex
(TSC), the effects are reversible, with rapid tumor regrowth upon halting treatment. This limited response is
due, at least in part, to the strictly cytostatic nature of rapalogs. In order to identify therapeutic strategies to
improve on mTOR inhibitors in both tumor syndromes and sporadic cancers, we must systematically define the
molecular response to mTOR inhibitors inherent to cells and tumors. Thus, in this project, we use both
hypothesis-driven and unbiased omics approaches to reveal the nature and consequences of network-wide
changes in transcription (Aim 1), tumor metabolism (Aim 2), and protein kinase signaling (Aim 3) upon
mTORC1 activation and inhibition. Our approaches combine reductionist cell and tissue models in Drosophila,
where the mTOR signaling network is very well conserved, with syngeneic mouse tumor models driven in part
by uncontrolled mTORC1 signaling. Within the broader context of this P01, this project is discovery-based and
foundational to the overarching goal of the program to define and target the signaling network that connects
the hamartoma syndrome tumor suppressors and mTORC1, impacting both genetic tumor syndromes and the
majority of sporadic cancers. The novel candidate targets and mechanisms revealed through our project serve
as a key point of integration for all 3 projects.

## Key facts

- **NIH application ID:** 10931455
- **Project number:** 5P01CA120964-17
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** David J. Kwiatkowski
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $468,591
- **Award type:** 5
- **Project period:** 2007-04-24 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931455

## Citation

> US National Institutes of Health, RePORTER application 10931455, Project 1: Identifying  new therapeutic avenues to selectively target tumors with uncontrolled mTORC1 activation (5P01CA120964-17). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10931455. Licensed CC0.

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