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

Award Number: R01CA275081
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/07/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $505,216 )
2025	2025	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	3	6/23/2025	NON-COMPETING CONTINUATION	$505,216
														Subtotal = $505,216

Issue Date FY: 2024 ( Subtotal = $479,955 )
2024	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Biology Research	000	2	6/20/2024	NON-COMPETING CONTINUATION	$479,955
														Subtotal = $479,955

Issue Date FY: 2023 ( Subtotal = $505,216 )
2023	2023	HEALTH RESEARCH, INC.	ELM & CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Biology Research	000	1	7/7/2023	NEW	$505,216
														Subtotal = $505,216

Grand Total All Awards = $1,490,387

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

Award Number: R01CA275081

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/07/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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