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Autophagy mediated immune stimulation by reovirus in KRAS mutated colorectal cancer

Award Number: R15CA267835
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/14/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Autophagy mediated immune stimulation by reovirus in KRAS mutated colorectal cancer - Project Summary The impressive success of cancer immune therapy reached its limitations and failed in its efficacy with immune deserted KRAS mutated tumors that constitute 45% of colorectal cancers. These patients have fewer treatment options necessitating the development of effective alternate therapy. Of late reovirus, with a double- stranded RNA genome, showed therapeutic efficacy in an oncogenic KRAS transformed colorectal tumors. Although previously studied for its oncolytic properties reovirus is being increasingly appreciated for its immune stimulation properties. However, its participation in immune stimulation, precisely utilizing two intimately related immune and autophagic modulatory pathways, remains largely unexplored. Preliminary results indicate that reovirus preferentially exploits the immune deserted mutant KRAS tumor microenvironment to successfully support its propagation in conjunction with destruction of the tumor cells. Furthermore, reovirus induces autophagy in KRAS mutated microenvironment. Knowledge gaps: It is crucial to understand the mechanism adopted by reovirus to facilitate the immune enrichment of mutant KRAS driven immune deserted microenvironment in colorectal cancer. The contribution of autophagic pathway in accentuating the process is unclear. Understanding the control mechanism between the autophagy and immune pathways is critical. Project hypothesis: The dual mode of action exerted by reovirus can be successfully translated to the clinic by augmenting the induction of the autophagy pathway. We propose to study the pattern of reovirus mediated induction of the autophagic machinery and determine how the molecular event is translated in improving the immune stimulation characteristics in KRAS mutated colorectal Cancer. In this context we will make use of KRAS mutant and wildtype colorectal cancer cell lines and our newly developed KPC:APC (tamoxifen- inducible KRAS-mutated colorectal cancer) mouse models along with the well-established syngeneic mouse model of colorectal cancer to mechanistically explore the process of crosstalk between the two pathways. Results will improve the understanding of the dynamics of KRAS mutated immune deserted cold tumors in facilitating reovirus to act as an immune stimulator Impact: This project will have dual impact of providing an enriched biomedical science related research environment to the aspiring undergraduate students as well as to directly address the clinical gap faced by the KRAS mutated colorectal cancer patients. Understanding the mechanism of cross talk between the autophagy and immune pathways followed by research supported recommendation of therapeutic induction of autophagy to improve immune therapy responsiveness of KRAS mutated colorectal cancer will be of paradigm clinical implications. In this pursuit we will AIM1: Demonstrate crosstalk between autophagy and immune pathways in reovirus treated KRAS mutant and wildtype colorectal cancer cell lines. AIM2: Examine if autophagy induction promotes reovirus mediated immune stimulation in KRAS mutated cold colorectal tumors in transgenic and syngeneic mouse models.


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 = $0 )
2025	2022	YESHIVA UNIVERSITY	500 W 185TH ST	NEW YORK	NY	10033	NEW YORK	USA	Cancer Biology Research	000	1	12/23/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $144,510 )
2024	2024	YESHIVA UNIVERSITY	500 W 185TH ST	NEW YORK	NY	10033	NEW YORK	USA	Cancer Biology Research	000	1	9/19/2024	SUPPLEMENT FOR EXPANSION	$144,510
														Subtotal = $144,510

Issue Date FY: 2022 ( Subtotal = $433,953 )
2022	2022	YESHIVA UNIVERSITY	500 W 185TH ST	NEW YORK	NY	10033	NEW YORK	USA	Cancer Biology Research	000	1	1/14/2022	NEW	$433,953
														Subtotal = $433,953

Grand Total All Awards = $578,463

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Autophagy mediated immune stimulation by reovirus in KRAS mutated colorectal cancer

Award Number: R15CA267835

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/14/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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