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Preclinical studies of KRAS and EGFR mutations in lung cancer PDXs

Award Number: U54CA233306
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Preclinical studies of KRAS and EGFR mutations in lung cancer PDXs - PROJECT SUMMARY/ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 22-039. Lung cancer is the leading cause of cancer incidence and mortality in all Americans but disproportionally high in communities of color. Compared to Whites, for example, African Americans and Latinos are 18% and 16% less likely to have an early lung cancer diagnosis, respectively. The 5-year survival of African Americans and Latinos is also 21% and 16% lower than White patients. However, the incidence and mortality rates in US minority populations are closely linked to their smoking rates. In African American and some Asian/Pacific Islander groups such as Hawaiian and Samoan, lung cancer is the top cause of cancer mortality. Lung cancer disproportionally affects African American men, who have incidence and mortality rates of 15% and 18% higher than White men. Even in Latinos, the ethnic group with the lowest smoking rates in the nation, lung cancer remains the first cause of cancer mortality in men. EGFR and KRAS are the most common mutations in lung tumors and are strongly associated with race, smoking, and genetic ancestry. KRAS is commonly diagnosed in Whites and African Americans, in men and smokers/former smokers. Asians and Latinos, on the other hand, have a significantly lower frequency of KRAS mutations but are enriched with mutations in EGFR. EGFR mutations in Asian and Latino patients are prevalent in never smoker women. Until recently, most of the targeted therapies for lung cancer were developed for EGFR mutant tumors, while KRAS was considered “undruggable.” This, however, changed in the last 12 months with the FDA approval of sotorasib, a molecule that increases overall response rate and progression-free survival in tumors carrying the KRAS G12C mutation. Despite these important advances, a significant fraction of patients either lack response or develop resistance to EGFR and KRAS targeted therapies. In this supplement, we are leveraging the resources of our minority PDX (MPDX) center to investigate mechanisms associated with response to inhibitors for KRAS and EGFR in models from White and minority patients. Our Specific Aims are as follows: Aim 1. To determine the activity of direct KRAS G12C inhibition of sotorasib in the presence or absence of dual inhibition of glycolysis and glutaminolysis with sapanisertib and telaglenastat (CB839) in KRAS G12C mutant PDXs with clinically relevant co-alterations (p53/Keap1). Aim 2. To carry out a feasibility study for identifying biomarkers associated with EGFR inhibitor resistance in lung PDXs from Asian and White patients. This project will increase our understanding of responses to targeted therapies for lunch cancer and serve as a springboard for future clinical trials on precision medicine in white and minority patients.


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 = -$186,293 )
2025	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	12/2/2024	SUPPLEMENT FOR EXPANSION	-$186,293
														Subtotal = -$186,293

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	002	1	4/4/2024	SUPPLEMENT FOR EXPANSION	$0
2024	2018	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	10/18/2023	NEW	$0
2024	2018	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	1	3/4/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $200,000 )
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	6/9/2022	SUPPLEMENT FOR EXPANSION	$200,000
														Subtotal = $200,000

Issue Date FY: 2020 ( Subtotal = $145,306 )
2020	2020	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Centers Support Grants	002	1	9/9/2020	SUPPLEMENT FOR EXPANSION	$0
2020	2020	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Centers Support Grants	001	1	9/3/2020	SUPPLEMENT FOR EXPANSION	$145,306
2020	2018	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	3/12/2020	NEW	$0
														Subtotal = $145,306

Issue Date FY: 2019 ( Subtotal = $334,871 )
2019	2019	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Cancer Centers Support Grants	001	1	9/17/2019	SUPPLEMENT FOR EXPANSION	$322,871
2019	2019	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	002	1	9/18/2019	SUPPLEMENT FOR EXPANSION	$12,000
2019	2018	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	11/27/2018	NEW	$0
														Subtotal = $334,871

Issue Date FY: 2018 ( Subtotal = $6,160,778 )
2018	2018	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	9/19/2018	NEW	$6,160,778
														Subtotal = $6,160,778

Grand Total All Awards = $6,654,662

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Preclinical studies of KRAS and EGFR mutations in lung cancer PDXs

Award Number: U54CA233306

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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