# Metabolic and Genetic Heterogeneity in Cancer

> **NIH NIH K00** · ROCKEFELLER UNIVERSITY · 2020 · $100,727

## Abstract

Project Summary: Metabolic and Genetic Heterogeneity in Cancer 
Targeting glucose metabolism in cancer is an attractive therapeutic area, but efforts to develop successful 
glycolytic inhibitors have failed. A major barrier in the cancer metabolism field is a systems-level 
understanding of the differential regulation of glycolysis that results from metabolic rewiring. This 
limitation prompted the investigation to determine whether metabolic control can be exploited for therapy. 
The hypothesis of the F99 phase is that rational targeting of pivotal enzymes that differentially regulate 
central carbon metabolism in cancer can result in anti-tumor efficacy and characterization of resistance 
mechanisms to glycolysis inhibition can advance the development of combination therapy. To address 
this hypothesis, Aim 1 characterizes the role of two important enzymes in central carbon metabolism, 3-
phosphoglycerate dehydrogenase (PHGDH) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) 
and how these enzymes can be targeted for cancer therapy. Sub-aim 1.1 uses CRISPR/Cas9 mediated 
PHGDH knockout (KO) to validate the selectivity and activity of two novel allosteric PHGDH inhibitors. 
Sub-aim 1.2 uses quantitative determinants of the Warburg Effect (WE) to reveal GAPDH as a rational 
therapeutic target, and comparative metabolomics to nominate KA as a potent GAPDH inhibitor in highly 
glycolytic cells, together uncovering metabolic predictors of drug response to GAPDH inhibition. These 
findings contribute to a shifting paradigm in the current understanding of metabolic cancer therapy and 
show the potential use of metabolic predictors, rather than genetic determinants, to predict response. 
Aim 2 will seek to characterize the resistance mechanisms to GAPDH inhibition in order to develop 
combination therapy and better understand the requirements of the WE. KA-sensitive cells will be made 
resistant and a lentiviral CRISPR/Cas9 sgRNA library loss-of-function screen will be employed to 
determine the metabolic enzymes driving resistance. The outcome will result in characterization of 
resistance development to glucose metabolism inhibition and the mechanism by which the WE occurs. 
In addition, since tumor heterogeneity largely contributes to limitations in drug targeting, there is an urgent 
need to better characterize the molecular determinants of microenvironment formation. The interplay 
among environmental factors, genetics, and epigenetics have recently been appreciated. The hypothesis 
of the K00 phase is that a dynamic cross-talk exists between oncogenic and epigenetic networks and is 
governed by tissue origin. Aim 3 will examine the role of oncogenic drivers and epigenetic regulators at 
different stages of cancer progression in different microenvironment settings to unravel the molecular 
components contributing to tumor heterogeneity. The outcome will establish a better understanding of 
the relationship between tumor heterogeneity and thera...

## Key facts

- **NIH application ID:** 9840887
- **Project number:** 5K00CA222986-04
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Maria V Liberti
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $100,727
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840887

## Citation

> US National Institutes of Health, RePORTER application 9840887, Metabolic and Genetic Heterogeneity in Cancer (5K00CA222986-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840887. Licensed CC0.

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