# Project 1: Targeting Metabolic Dependencies in PDAC

> **NIH NIH P01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $351,368

## Abstract

Abstract - Project 1 (Targeting Metabolic Dependencies in PDAC) 
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States 
with a median survival of less than 6 months and a dismal 5-year survival rate of 7%. The highly malignant 
nature of PDAC is largely the result of driving oncogenic Kras mutations (Kras*) in >90% of tumors, as well as 
the heterogeneous nature of the disease at both the genomic and cellular levels. To date, no drug directly 
targeting Kras* has reached the clinic, and inhibitors of Kras* effector pathways in clinical trials have achieved 
only minimal responses followed by relapse of aggressive disease. Furthermore, immune targeting of PDAC 
has so far been unsuccessful. Thus, a critical need remains to identify new therapeutic vulnerabilities in PDAC. 
In our previous grant cycle, Project 1 and our P01 team established a role for Kras* in tumor maintenance in 
vivo wherein it controlled key metabolism enzymes supporting cancer-relevant anabolic processes that, in turn, 
are required for Kras*-driven PDAC maintenance. Using our inducible Kras* PDAC model, we also identified a 
subset of tumor cells with tumor-initiating cell (TIC) properties that can survive Kras* extinction and may lead to 
tumor recurrence following oncogene ablation. One of the hallmarks of these Kras* extinction-resistant cells 
(KRCs) is the shift from aerobic glycolysis to mitochondrial oxidative metabolism to sustain cell viability. Our 
P01 team further demonstrated that, while PDAC exhibits high basal autophagy, autophagic flux in KRCs was 
further enhanced to supply substrate for mitochondrial oxidative phosphorylation (OXPHOS), and targeting 
autophagy or OXPHOS effectively eliminated KRCs to prevent tumor relapse. Therefore, the collaborative work 
from our P01 team strongly suggests that effective therapeutics for PDAC should target not only players 
essential for Kras*-dependent tumor maintenance, but also pathways required to maintain KRCs. These data 
are the basis for an initiative begun during the last grant cycle to develop a novel OXPHOS inhibitor compound 
in PDAC, IACS-10759, at the Institute for Applied Cancer Science. In this next cycle, Project 1 will continue our 
efforts to better define the metabolism programs that sustain Kras*-dependent tumors as well as KRCs and to 
explore the translational potential of targeting metabolic processes, including targeting OXPHOS with IACS- 
10759. Project 1 will work closely with the Cores, which have extensive expertise in pathology, preclinical 
therapeutics, and computational biology, and will be highly integrated with Project 2 to characterize the role of 
autophagy-regulating pathways. Our studies will also integrate with Project 3, using our inducible Kras* mouse 
model to explore the effects of Kras*-dependent and –independent metabolism programs on tumor immunity 
and response to immune checkpoint therapy. The knowledge gained from these hi...

## Key facts

- **NIH application ID:** 9904491
- **Project number:** 5P01CA117969-15
- **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:** 2020
- **Award amount:** $351,368
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904491

## Citation

> US National Institutes of Health, RePORTER application 9904491, Project 1: Targeting Metabolic Dependencies in PDAC (5P01CA117969-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9904491. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*