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Exploring the impact of HSP90 inhibition on antigen presentation and anti-tumor immune responses

Award Number: R00CA241072
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/02/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Exploring the impact of HSP90 inhibition on antigen presentation and anti-tumor immune responses - Project Summary/Abstract Immunotherapies designed to stimulate anti-tumor immune responses by enhancing CD8+ T-cell activity have revolutionized the treatment of cancer, but many patients do not respond. Robust CD8+ T-cell recognition of tumors requires the presentation of cellular antigens on Major Histocompatibility Complex I (MHC-I) and many cancers suppress MHC-I presentation as a means of evading immune detection and acquiring resistance to immunotherapy. This proposal outlines experiments to explore a mechanistically distinct method of stimulating antigen presentation by disrupting protein-folding pathways. The heat shock protein 90 kDa (HSP90) is a molecular chaperone that is known to regulate the stability of numerous cellular proteins, termed HSP90 “clients”, including proteins involved in oncogenic signaling pathways. Perhaps most interestingly, HSP90 is particularly important for maintaining the conformational stability of mutated proteins. Therefore, inhibition of HSP90 function represents a unique strategy for destabilizing the mutant proteomes of cancer cells to reveal them to the immune system. While numerous HSP90 inhibitors have been tested clinically as a means to disrupt oncogenic signaling and kill cancer cells, none have been FDA approved. Preliminary data demonstrate that in contrast to clinically tested dosing strategies, continuous, low dose exposure to HSP90 inhibitors stimulates MHC-I antigen presentation and drives anti-tumor immune responses in a syngeneic mouse model through a mechanism that is fundamentally distinct from high dose HSP90 inhibitor treatment. However, the mechanism of MHC-I induction and the relationship between HSP90 clients and MHC-I antigens is unknown. Using pharmacological, genetic, and proteomic tools, this proposal will uncover the mechanism driving MHC-I induction following low dose HSP90 inhibitor treatment. Furthermore, experiments in genetically engineered mouse models of lung adenocarcinoma and colorectal cancer will investigate the consequences of this treatment strategy on antigen presentation and anti-tumor immune responses in vivo. Taken together, this study will evaluate low dose HSP90 inhibition as a mechanistically distinct method to induce MHC-I antigen presentation and reveal mutated cancer cell proteomes to the immune system, and also provide support for repurposing orally bioavailable HSP90 inhibitors as a new class of immunomodulatory agents. This proposal also outlines career objectives and goals in preparation for obtaining a faculty position. Notably, the career development plan identifies key areas for training in tumor immunology, animal modeling, mentorship of trainees, and oral and written scientific communication. The training activities are designed to build skills, both scientific and professional, that are required for running an independent laboratory. Finally, the complementary expertise of the co-sponsors, the advisory team, and rich scientific environment at MIT are uniquely suited to ensure success of the proposed research and career development goals. !


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 = -$2,939 )
2025	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Research Manpower	000	5	6/10/2025	NON-COMPETING CONTINUATION	-$2,939
														Subtotal = -$2,939

Issue Date FY: 2024 ( Subtotal = $248,999 )
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Research Manpower	001	5	4/17/2024	NON-COMPETING CONTINUATION	$24,900
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Research Manpower	000	5	2/8/2024	NON-COMPETING CONTINUATION	$224,099
														Subtotal = $248,999

Issue Date FY: 2023 ( Subtotal = $248,999 )
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Research Manpower	000	4	2/27/2023	NON-COMPETING CONTINUATION	$248,999
														Subtotal = $248,999

Issue Date FY: 2022 ( Subtotal = $244,018 )
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Research Manpower	000	3	4/27/2022	EXTENSION WITH OR WITHOUT FUNDS	$244,018
														Subtotal = $244,018

Grand Total All Awards = $739,077

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Exploring the impact of HSP90 inhibition on antigen presentation and anti-tumor immune responses

Award Number: R00CA241072

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/02/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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