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Mechanistic insights into Variants of Uncertain Significance (VUS) using novel EGFR variants as a paradigm

Award Number: R01CA227833
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/19/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Mechanistic insights into Variants of Uncertain Significance (VUS) using novel EGFR variants as a paradigm - Mechanistic insights into Variants of Uncertain Significance (VUS) using novel EGFR variants as a paradigm Investigators: Christine M. Lovly, MD, PhD and Jens Meiler, PhD The prospective identification and rational therapeutic targeting of tumor genomic alterations has revolutionized the care of patients with lung cancer and is now the accepted standard of care for patients with this disease and with other tumor types. With the advent of sophisticated tumor genotyping, the discovery of novel genetic variants is accelerating. In order to realize the promise of precision medicine, there is an urgent need to define the actionability of these variants to select targeted inhibitors. The objective of this proposal is to develop a novel, data-driven paradigm for characterizing genomic Variants of Uncertain Significance (VUS) and generating actionable hypotheses about their functions. For this purpose, we propose an innovative `Personalized Structural Biology' approach. The central hypothesis of this paradigm is that VUS can be best understood by placing the mutation into the context of protein structures and inferring from the structural consequences of the mutation on function, phenotype, and drug sensitivity. By analyzing the tumors of patients with lung cancer, we have identified three EGFR genomic alterations that have not previously been reported: 1) EGFR exon 18-25 Kinase Domain Duplication, 2) EGFR- RAD51 fusions, and 3) EGFR transmembrane domain mutations. Importantly, each of these EGFR variants was reported as a VUS on clinical genotyping reports because there were no data regarding the sensitivity of the mutated proteins to EGFR inhibitors now used in clinical practice. We sought to study these EGFR VUS in an effort to understand on a fundamental mechanistic level how they activate the EGF receptor to promote oncogenesis. We will integrate structural and computational modeling with various biochemical, molecular, cell based, and in vivo approaches to investigate the functional effects of these three distinct alterations. Through these studies, we expect to define previously unrecognized mechanisms of oncogenesis in lung cancer defined by these novel and recurrently detected EGFR variants. Importantly, understanding the structural and functional consequences of these EGFR variants is expected to provide novel insights into ErbB receptor biology and reveal new uses for FDA approved agents in lung cancer and many other tumor types which harbor ErbB (EGFR/HER2/HER3/HER4) alterations. Furthermore, a key deliverable of the proposed studies is the development of an innovative, integrated in silico pipeline that is applicable to VUS in any type of cancer, which we will make freely available via RosettaCommons (www.rosettacommons.org). Thereby, the impact of the proposed research will go beyond that of the three EGFR variants discussed in this proposal. With the recent FDA approval of NGS-based tumor testing, the problem of VUS will continue to grow as these large (>300) gene panel clinical diagnostic assays are reaching higher volumes of patients. Therefore, it is imperative the field generate and systematically integrate such `personalized structural biology' methods to understand the functional significance of VUS in order to best serve all cancer 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: 2026 ( Subtotal = -$339,750 )
2026	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	000	5	11/20/2025	NON-COMPETING CONTINUATION	-$339,750
														Subtotal = -$339,750

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	000	5	9/16/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $331,530 )
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	002	5	7/21/2023	NON-COMPETING CONTINUATION	$316,483
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	003	5	7/25/2023	SUPPLEMENT FOR EXPANSION	$15,047
2023	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	000	4	5/26/2023	NON-COMPETING CONTINUATION	$0
2023	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	001	4	5/26/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $331,530

Issue Date FY: 2022 ( Subtotal = $370,416 )
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	001	4	8/30/2022	SUPPLEMENT FOR EXPANSION	$50,818
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	000	4	4/15/2022	NON-COMPETING CONTINUATION	$319,598
														Subtotal = $370,416

Issue Date FY: 2021 ( Subtotal = $343,923 )
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	000	3	3/29/2021	NON-COMPETING CONTINUATION	$343,923
														Subtotal = $343,923

Issue Date FY: 2020 ( Subtotal = $346,920 )
2020	2020	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	000	2	3/24/2020	NON-COMPETING CONTINUATION	$346,920
														Subtotal = $346,920

Issue Date FY: 2019 ( Subtotal = $352,184 )
2019	2019	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Biology Research	000	1	4/19/2019	NEW	$352,184
														Subtotal = $352,184

Grand Total All Awards = $1,405,223

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Mechanistic insights into Variants of Uncertain Significance (VUS) using novel EGFR variants as a paradigm

Award Number: R01CA227833

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/19/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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