# Impact of RB activation on the pancreatic cancer epigenome and tumor microenvironment

> **NIH NIH R01** · ROSWELL PARK CANCER INSTITUTE CORP · 2024 · $479,955

## Abstract

Pancreatic ductal adenocarcinoma (PDAC) represents a therapy recalcitrant disease with 5-year survival rate of
approximately 10%. Multiple failed clinical trials reinforce the need for new approaches to treatment that employ
rationally developed therapies targeting key genetic features of PDAC tumors as well as the tumor
microenvironment. Fundamentally PDAC is a KRAS-driven tumor; however, approaches to target KRAS either
genetically or pharmaceutically have led to the realization that tumors can evolve mechanisms to continue cell
division in the presence of such interventions. Using a combination of unbiased analyses and patient derived
models we find that most tumors have evolved mechanisms to deregulate the retinoblastoma tumors suppressor
(RB) pathway that limits the effectiveness of targeting RAS or effector pathways (e.g. MEK inhibition).
Consequently, the activation of RB is sufficient to limit the proliferation and tumorigenic growth of PDAC models.
In addition to effects on the proliferation, we have found that RB activation is sufficient to coordinate changes in
gene expression that impact on genes related to classical vs. basal subtypes of PDAC and immunological gene
expression programs (e.g. antigen presentation and interferon response). Unlike cell cycle responses, these
changes in gene expression are more heterogeneous and the underlying mechanisms and key regulatory
elements remain poorly understood. In Aim 1 we will delineate the RB regulation and mechanisms of gene
expression regulation in PDAC models. While RB status clearly has effects on tumor cell division, an important
element of RB-pathway activation are effects related to the tumor microenvironment. Preliminary and published
data indicate that RB activation has broad effects on the tumor stroma and immunological milieu. Much of these
studies have employed systemic strategies that impact on both the tumor and the host. In preliminary data, we
have found that activation of RB selectively within the tumor is sufficient to change the fibroblastic and
immunological cell subtypes with the tumor, albeit not at the same level of systemic treatments. Here we will
interrogate the intersection between the tumor and the microenvironment and how these impact tumor-static
response and can be exploited by immunotherapy approaches. Together, Aim 2 will define the impact of RB-
activation on the tumor microenvironment using a combination of immune competent models and clinical
specimens.

## Key facts

- **NIH application ID:** 10884406
- **Project number:** 5R01CA275081-02
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** Erik Knudsen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $479,955
- **Award type:** 5
- **Project period:** 2023-07-07 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884406

## Citation

> US National Institutes of Health, RePORTER application 10884406, Impact of RB activation on the pancreatic cancer epigenome and tumor microenvironment (5R01CA275081-02). Retrieved via AI Analytics 2026-06-04 from https://api.ai-analytics.org/grant/nih/10884406. Licensed CC0.

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