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Therapeutic dissection of genotype-specific lung cancer vulnerabilities

Award Number: F32CA236311
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2021

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Therapeutic dissection of genotype-specific lung cancer vulnerabilities - Lung cancer causes more deaths worldwide than the next top three cancers combined. While targeting oncogenic drivers has shown widespread clinical utility, therapeutic responses have also been associated with tumor suppressor genotypes. Despite advances in clinical cancer genome sequencing and the development of many targeted therapies, understanding the relationship of tumor genotype to therapeutic responses remains a major obstacle to translating existing drugs into effective cancer treatments. There is a growing appreciation in cancer biology for the importance of the tumor microenvironment in cancer growth and therapy responses, underscoring the need to assess tumor response to therapy in the native tumor microenvironment. Genetically- engineered mouse models have emerged as particularly rigorous systems with which to test oncology therapies. However, a major limitation of existing mouse model is the relatively small number of different genotypes that can be generated. We have established a novel multiplexed somatic genome-editing approach that will allow the quantification of genotype-specific drug responses. This in vivo approach will increase the precision and scope of translational cancer pharmacogenomics studies. To quantify the effect of tumor suppressor gene inactivation on lung cancer growth in a high-throughput manner, I will use a method combining somatic Cas9-mediated gene inactivation with existing genetically-engineered mouse models, to generate 12 different lung tumor genotypes in parallel in individual mice. To quantify the exact size of each tumor and determine the size distribution of each genotype of tumors, I will induce tumors with barcoded vectors and use high-throughput sequencing and statistical approaches to determine the number of cancer cells in each tumor. I will quantify the responses of different genotypes of tumors to several therapies that have been shown to have genotype-specific effects in lung adenocarcinoma models. This will extend our understanding of the genetic determinants of treatment responses and define the experimental and statistical parameters to enable the most efficient use of these models for translational studies. By performing pre-clinical trials for targeted therapies across different tumor genotypes in parallel, I will generate a pharmacogenomic map connecting lung adenocarcinoma genotype to targeted therapy response. I will uncover sensitive and resistant genotypes, validate these genotype-specific effect, and investigate the cellular and molecular mechanisms of drug sensitivity and resistance. My studies will uncover novel biological insights that enable designing combinatorial therapy or developing novel therapies in order to overcome therapy resistance.


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: 2023 ( Subtotal = -$35,962 )
2023	2021	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	3	5/12/2023	NON-COMPETING CONTINUATION	-$24,266
2023	2021	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	001	3	5/15/2023	NON-COMPETING CONTINUATION	-$35,962
2023	2021	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	002	3	6/14/2023	NON-COMPETING CONTINUATION	$24,266
														Subtotal = -$35,962

Issue Date FY: 2021 ( Subtotal = $67,562 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	3	6/1/2021	NON-COMPETING CONTINUATION	$67,562
														Subtotal = $67,562

Issue Date FY: 2020 ( Subtotal = $64,310 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	2	4/22/2020	NON-COMPETING CONTINUATION	$64,310
														Subtotal = $64,310

Issue Date FY: 2019 ( Subtotal = $61,226 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	001	1	12/17/2018	NEW	$0
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	1	12/17/2018	NEW	$61,226
														Subtotal = $61,226

Grand Total All Awards = $157,136

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Therapeutic dissection of genotype-specific lung cancer vulnerabilities

Award Number: F32CA236311

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2021

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