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Identifying novel therapies targeting Merkel cell carcinoma and tumor microenvironment

Award Number: R01CA266514
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/14/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Identifying novel therapies targeting Merkel cell carcinoma and tumor microenvironment - ABSTRACT 1 Merkel cell carcinoma MCC is an often-lethal skin cancer with increasing incidence and few treatment 2 options. The dismal five-year survival rate of advanced MCC is less than 18% and the mortality rate is 3-times 3 higher than melanoma. Although immune checkpoint inhibitors (ICI) have become standard of care in advanced 4 MCC, 50% of all MCC patients are ineligible for ICIs and resistance develops in the majority of treated patients. 5 Importantly, there is no therapeutic alternative for these patients. Given this urgent clinical demand, our long- 6 term goal is to identify novel therapies which can be used to augment ICI efficacy and overcome ICI resistance, 7 or to serve as alternative treatments for MCC patients who are ineligible for ICIs. Utilizing MCC cell lines 8 established in our laboratory and high throughput dose-response drug screening of 430 clinically relevant 9 kinase inhibitors, we identified fimepinostat, the first-in-class PI3K/HDAC inhibitor, with potent anti-MCC 10 activities. The objective of this proposal is to determine therapeutic efficacy of fimepinostat alone and in 11 combination with ICIs, and resolve intrinsic and extrinsic mechanisms of anti-MCC activities. The central 12 hypothesis is that fimepinostat inhibits MCC growth and progression by targeting PI3K and HDAC epigenetic 13 pathways, and by sensitizing tumor cells to ICIs through augmentation of antitumor immunity in the MCC 14 microenvironment. We will test this hypothesis by utilizing systems-level approaches integrating cellular, 15 molecular and imaging analyses in single cell resolution to fully study the functional complexity of the MCC 16 ecosystem in our clinically relevant animal model representing the closest preclinical models of human MCC- 17 immune microenvironment. This singularly powerful biological platform will enable us to study direct effects of 18 fimepinostat on tumors and tumor-immune interactions as a monotherapy and in combination with 19 immunotherapy, as well as uncover new insights into TME-mediated resistance and response. The proposed 20 research is significant because successful completion of the project will lay foundation for a new treatment 21 paradigm for MCC, overcoming or circumventing current limitations in therapeutic options, and lending insights 22 into immune resistance will be applicable across human cancers and improve patient outcomes.


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 = $384,870 )
2025	2025	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST BLDG 167T	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Treatment Research	000	4	6/10/2025	NON-COMPETING CONTINUATION	$384,870
														Subtotal = $384,870

Issue Date FY: 2024 ( Subtotal = $362,472 )
2024	2024	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Treatment Research	000	3	6/21/2024	NON-COMPETING CONTINUATION	$362,472
														Subtotal = $362,472

Issue Date FY: 2023 ( Subtotal = $379,343 )
2023	2023	SOUTHERN CALIFORNIA INSTITUTE FOR RESEAR	5901 E 7TH ST	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Treatment Research	000	2	6/30/2023	NON-COMPETING CONTINUATION	$379,343
														Subtotal = $379,343

Issue Date FY: 2022 ( Subtotal = $384,870 )
2022	2022	SOUTHERN CALIFORNIA INSTITUTE FOR RESEARCH AND EDUCATION	5901 E 7TH ST 151	LONG BEACH	CA	90822	LOS ANGELES	USA	Cancer Treatment Research	000	1	7/14/2022	NEW	$384,870
														Subtotal = $384,870

Grand Total All Awards = $1,511,555

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Identifying novel therapies targeting Merkel cell carcinoma and tumor microenvironment

Award Number: R01CA266514

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/14/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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