# Project 2: Identifying Metabolic vulnerabilities and targets in cancers with mutations in hamartoma genes

> **NIH NIH P01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $524,400

## Abstract

Project 2: Abstract
The hypothesis guiding this proposal is that mutations in hamartoma syndrome genes (PTEN, LKB1, TSC1,
TSC2) dominantly rewire metabolism exposing unique vulnerabilities. The focus of this project is to better
understand the molecular and biochemical basis for the metabolic vulnerabilities and provide preclinical data
that would support the development of biomarker driven clinical trials to evaluate such drugs in patients with
germline or the many tumors containing sporadic mutations in hamartoma syndrome genes. We have
decoded the optimal substrate motif for every single mammalian protein kinase in the last funding period and
made an algorithm that allows us to decode which kinases are active or inactive in a given biological samples
based on unbiased phospho-proteomics. Here we will focus on use of this new method to identify new
metabolic enzymes targeted by LKB1-dependent kinases. The specific aims are: 1) Defining critical kinase-
substrate interactions deregulated in hamartoma genes in cell lines and tissues; 2) Defining metabolic
vulnerabilities deregulated in hamartoma genes in cell lines and tissues; and 3) Defining how AMPK control of
TFEB contributes to the survival of hamartoma cells and how to target tumors based on new understanding of
this pathway.

## Key facts

- **NIH application ID:** 10931460
- **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:** $524,400
- **Award type:** 5
- **Project period:** 2007-04-24 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931460

## Citation

> US National Institutes of Health, RePORTER application 10931460, Project 2: Identifying Metabolic vulnerabilities and targets in cancers with mutations in hamartoma genes (5P01CA120964-17). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10931460. Licensed CC0.

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