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Overcoming Tumor-Intrinsic Therapeutic Resistance to Immunotherapies

Award Number: R21CA259721
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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Overcoming Tumor-Intrinsic Therapeutic Resistance to Immunotherapies - PROJECT SUMMARY/ABSTRACT Immune checkpoint blockers (ICBs) such as anti-CTLA-4 and anti-PD-1 are revolutionizing the field of cancer care, emerging as the fourth pillar of cancer therapies. To date, more than 60 approvals of utilizing ICBs to treat various types of cancer have been granted by the FDA. Despite their transformative response, the overall efficacy of ICBs is limited to a small subset of cancer patients, because of therapeutic resistance. We and others recently found that loss of IFN- signaling genes in advanced melanoma and colon cancer is a major mechanism of resistance to ICBs. Therefore, identifying therapeutic strategies capable of overcoming this resistance is of utmost importance. Based on our preliminary data, we hypothesize that deletion of IFN- signaling in tumor cells (IFNR1KO) augments the Myc-glutaminolysis pathway and metabolically forges an “immune-cold” tumor microenvironment, conferring therapeutic resistance to ICBs. In Aim 1, we will determine metabolic mechanisms by which the IFNR1-Myc axis regulates therapeutic response to ICBs in both mouse and human melanoma. In Aim 2, we will dissect cellular mechanisms by which the IFNR1-Myc axis mediates ICB resistance, and attempt to target Myc-driven metabolic pathways to overcome ICB resistance. We will also test these metabolic modulators as potential effective strategies to sensitize “immune cold” IFNR1KO tumors to ICBs. While metabolic reprogramming in tumor cells has been correlated with therapeutic resistance to chemotherapies, to the best of our knowledge, there is no prior study directly linking metabolic reprogramming to therapeutic resistance to ICBs. As such, we predict insights gained from our studies will significantly advance our understanding of how metabolic reprograming associated with tumor-intrinsic alterations coordinates therapeutic responses of ICBs. These studies may manifest “targeted” therapies for cancer patients who are resistant to ICBs.


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: 2024 ( Subtotal = -$130 )
2024	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Treatment Research	000	2	5/2/2024	NON-COMPETING CONTINUATION	-$130
														Subtotal = -$130

Issue Date FY: 2023 ( Subtotal = $204,106 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Treatment Research	001	2	3/15/2023	NON-COMPETING CONTINUATION	$16,662
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Treatment Research	000	2	11/28/2022	NON-COMPETING CONTINUATION	$187,444
														Subtotal = $204,106

Issue Date FY: 2022 ( Subtotal = $173,559 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Treatment Research	000	1	11/24/2021	NEW	$173,559
														Subtotal = $173,559

Grand Total All Awards = $377,535

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Overcoming Tumor-Intrinsic Therapeutic Resistance to Immunotherapies

Award Number: R21CA259721

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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