# Project 2-Identifying and exploiting metabolic vulnerabilities in PDAC

> **NIH NIH P01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $731,128

## Abstract

Project 2 -­ Abstract/Summary 
 
Our  mechanistic  work  has  established  general  principles  of  metabolic  reprogramming  in  PDAC,  revealing 
therapeutic  insights that show dramatic effects  in preclinical  models  (alanine  metabolism  blockade)  as  well  as 
benefit in the clinic (autophagy inhibition). In this next cycle, we seek to address two key questions to enable us 
to  most effectively define and  exploit  metabolic  vulnerabilities  in PDAC.  First, how  do  the  different  concurrent 
cancer gene mutations that define PDAC subsets influence cancer cell metabolism and the metabolic interplay 
with  the  TME?  Secondly,  what  role  does  regulation  of  mitochondria,  organelles  central  to  integration  of 
metabolism and innate immune signals, play in metabolic reprogramming and cancer-­stroma cell interactions in 
genetic subsets of Kras* PDAC? By developing a series of novel GEM models and patient-­derived KRAS* PDAC 
models  representing  major  genotypes,  we  have  identified  pronounced  genetically-­driven  differences  in  tumor 
cell metabolism and cancer-­immune cell interactions. We hypothesize that cooperating genetic alterations drive 
distinct  metabolic  programs  and  associated  vulnerabilities  in  cancer  cells.  Moreover,  we  predict  that  immune 
differences  will  further  influence  cancer  cell  metabolism  in  these  distinct  genetic  settings.  To  address  these 
hypotheses,  we  propose  the  following  aims:  #1  Determine  the  influence  of  major  PDAC  gene  mutations  on 
metabolic  programs;;  #2  Assess  role  of  the  autophagy/lysosome  system  on  tumor-­TME  crosstalk  in  genetic 
subsets of PDAC;; and, #3 Investigate mitochondrial regulation and relationship to metabolism and inflammatory 
signaling in PDAC subsets.

## Key facts

- **NIH application ID:** 10170990
- **Project number:** 2P01CA117969-16
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** RONALD ANTHONY DEPINHO
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $731,128
- **Award type:** 2
- **Project period:** 2005-12-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170990

## Citation

> US National Institutes of Health, RePORTER application 10170990, Project 2-Identifying and exploiting metabolic vulnerabilities in PDAC (2P01CA117969-16). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10170990. Licensed CC0.

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