# Project 3: The Functional Contribution of Tumor Immunity in PDAC

> **NIH NIH P01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $319,026

## Abstract

Abstract – Project 3 (The Functional Contribution of Tumor Immunity to PDAC) 
PDAC is marked by an extensive desmoplastic reaction/stroma consisting of myofibroblasts, extracellular 
matrix (ECM) and immune cells, and oncogenic Kras is a critical driver of PDAC genesis and maintenance. 
The functional importance of PDAC microenvironment and its various cellular constituent in oncogenic Kras 
dependent and independent PDAC maintenance remains an area of active investigation, but there is minimal 
knowledge addressing the role of oncogenic Kras in shaping tumor immunity, in particular the T cell response. 
The central mission of our P01 program is to collectively identify a range of novel Kras driven vulnerable nodes 
that can be inhibited as a treatment for this devastating disease. The inducible oncogenic Kras genetically 
engineered mouse model (GEMM) of PDAC indicated that tumor regression could be achieved via oncogenic 
Kras extinction, a process accompanied by depletion of oncogenic Kras dependent cancer cells and significant, 
albeit incompletely characterized, alterations in immune response. Studies from Projects 1 and 2 using this 
PDAC GEMM also offered mechanistic insights into spontaneous tumor relapse, which includes the presence 
oncogenic Kras extinction resistant cells (KRC) with distinct metabolic dependencies (OXPHOS), and the 
emergence of tumors with activation of YAP or other yet unidentified mechanism for PDAC maintenance. 
Projects 1 and 2 will focus on exploiting the metabolic vulnerabilities of cancer cells and the central hypothesis 
of Project 3 is that “oncogenic Kras and its signaling surrogates have a causal effect on tumor immunity to 
facilitate cancer progression”. Knowledge of this oncogenic Kras driven circuitry may illuminate therapeutic 
points of intervention in the tumor microenvironment and offer an improved understanding of how to deploy 
checkpoint blockade therapies in combination with cancer cell-specific therapies targeting metabolic or salvage 
pathways. The study could inform combination treatment that includes checkpoint blockade therapies – i.e., 
whether OXPHOS inhibition or autophagy inhibition can help or impede such immunotherapy strategies. The 
studies proposed by Project 3 are highly interconnected with studies proposed in Projects 1 and 2, and rely 
directly on all the Cores of this P01. Specifically, the integrated specific aims of Project 3 are to investigate 
Kras* dependent and independent immune response in PDAC (Aim 1), to determine the impact of targeting 
metabolic and salvage pathways on tumor immunity (Aim 2) and to identify novel strategies to enhance 
efficacy of checkpoint blockade immunotherapy in PDAC (Aim 3). This effort is integral to the overall P01 
Program Goal of developing a mechanism-based rational combination strategy that can lead to meaningful 
therapeutic advances for PDAC patients.

## Key facts

- **NIH application ID:** 9904493
- **Project number:** 5P01CA117969-15
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** RAGHU KALLURI
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $319,026
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904493

## Citation

> US National Institutes of Health, RePORTER application 9904493, Project 3: The Functional Contribution of Tumor Immunity in PDAC (5P01CA117969-15). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9904493. Licensed CC0.

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