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Functional Characterization of HER Family Variant Biology and Resistance in Cancer

Award Number: R00CA248836
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Functional Characterization of HER Family Variant Biology and Resistance in Cancer - Project Summary/Abstract Dr. Tikvah Hayes is a postdoctoral research fellow in the laboratory of Dr. Matthew Meyerson at the Dana-Farber Cancer Institute and the Broad Institute. Her long-term career goal is to reduce cancer-associated mortality and suffering by determining the mechanisms of cancer development and identifying attractive therapeutic strategies for better patient care. To accomplish this goal, Dr. Hayes uniquely leverages both functional genomics and molecular biology methods to answer fundamental questions related to cancer biology. The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases (RTK) is frequently altered in cancer. Targeted panel sequencing of patient tumors has revealed a number of activating alterations in both EGFR and HER2. As a consequence, several generations of molecularly targeted EGFR and HER2 therapies have been designed and have proved efficacious for some patients with either EGFR- or HER2-mutant cancers. However, a subset of patient-observed HER family variants lacking a reported function persist and in the absence of functional data are classified as variants of unknown significance. It remains unknown whether all EGFR and HER2 missense mutations are oncogenic drivers and are sensitive to clinical EGFR or HER2-targeted therapies. This proposal aims to functionally and mechanistically characterize the role of EGFR and HER2 missense variants in promoting oncogenesis and resistance to tyrosine kinase inhibitor (TKI) therapies. Aim 1 will seek to nominate alternative strategies for patients harboring rare EGFR mutations where no clinically approved EGFR- targeted therapy exists. Aim 2 will evaluate the oncogenic capacity of rare EGFR variants. Finally, in Aim 3, HER2 variant oncogenic capacity and TKI sensitivity will be interrogated. The proposed research will greatly improve our understanding of how RTK missense variants promote cancer development and resistance to targeted therapies. Dr. Hayes will learn new techniques which will include organoid culturing, in vivo cell line xenografts, intrathoracic lung injections, tumor imaging and tissue processing/staining, while simultaneously enhancing her career development through training in grant-writing, science communication, and leadership. During the K99 phase, Dr. Hayes’ research and training will be carried out under the primary mentorship of Dr. Matthew Meyerson, a leader in cancer genomics, and will be additionally complemented by collaborations with experts in high- throughput genetic screening, clinical genomics, structural biology, and in vivo mouse modeling, as well as mentoring from an advisory committee consisting of Drs. Michael Eck, William Hahn, Pasi Janne, and Carla Kim.


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 = $207,616 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Research Manpower	000	5	7/29/2025	NON-COMPETING CONTINUATION	$207,616
														Subtotal = $207,616

Issue Date FY: 2024 ( Subtotal = $290,384 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Research Manpower	002	4	9/9/2024	NON-COMPETING CONTINUATION	$249,000
2024	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Research Manpower	001	3	4/23/2024	EXTENSION WITH OR WITHOUT FUNDS	$41,384
2024	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Research Manpower	000	3	1/10/2024	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $290,384

Issue Date FY: 2023 ( Subtotal = $248,999 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Research Manpower	001	3	9/14/2023	EXTENSION WITH OR WITHOUT FUNDS	$0
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Research Manpower	000	3	9/11/2023	EXTENSION WITH OR WITHOUT FUNDS	$248,999
														Subtotal = $248,999

Grand Total All Awards = $746,999

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Functional Characterization of HER Family Variant Biology and Resistance in Cancer

Award Number: R00CA248836

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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