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(PQ4) Quantitative and multiplexed analysis of gene function in cancer in vivo

Award Number: R01CA231253
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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(PQ4) Quantitative and multiplexed analysis of gene function in cancer in vivo - PROJECT SUMMARY Genome sequencing has catalogued the somatic alterations in human cancers and identified many putative driver genes. However, human cancers generally evolve through the sequential acquisition of multiple genomic alterations and simply identifying recurrent genomic alterations does not necessarily reveal their functional importance to cancer growth. Genetically engineered mouse models have become a mainstay for the analysis of gene function in cancer in vivo, however the breadth of their utility is limited by the fact that they are neither readily scalable nor sufficiently quantitative. To increase the scope and precision of in vivo cancer modeling, we previously integrated conventional genetically-engineered mouse models, CRISPR/Cas9-based somatic genome engineering, and quantitative genomics with mathematical approaches. We developed methods to inactivate multiple genes in parallel in mouse models of lung cancer using pools of barcoded sgRNA- containing lentiviral vectors. This tumor barcoding with sequencing (Tuba-seq) approach uncovers the size of each tumor, enables the parallel investigation of multiple tumor genotypes in individual mice, and allows the generation of large-scale maps of gene function within autochthonous cancer models. Our preliminary data and novel genetic systems, as well as our dedicated and collaborative team of investigators with expertise in cancer genetics, mouse models, genome-editing, clinical cancer care, and quantitative modeling make us uniquely positioned to conduct these studies. In this proposal, we will extend Tuba-seq to quantify the effect of combinatorial genetic alterations through the development and validation of a platform for the rapid and quantitative analysis of interactions between genetic alterations on tumor growth in vivo. To enable multiplexed and quantitative analysis of the impact of temporally controlled genomic alterations on cancer cell growth in vivo, we will also develop a system for inducible genome editing in established lung tumors. Finally, we will develop novel in vivo approaches to comprehensively and broadly uncover the gene expression programs in cancer cells of different genotypes in parallel. Through multiplexed in vivo genetic alterations, the effect of putative cancer drivers can be uncovered at an unprecedented scale and resolution. The results of this proposal will be significant because innovative methods for the cost-effective, quantitative, and multiplexed analysis of the genetic determinants of cancer pathogenesis will illuminate novel aspects of tumorigenesis and accelerate our ability to understand cancer evolution, drug responses, and 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: 2025 ( Subtotal = $0 )
2025	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	5	11/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $446,368 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	5	8/16/2022	NON-COMPETING CONTINUATION	$446,368
														Subtotal = $446,368

Issue Date FY: 2021 ( Subtotal = $461,991 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	4	8/13/2021	NON-COMPETING CONTINUATION	$461,991
														Subtotal = $461,991

Issue Date FY: 2020 ( Subtotal = $461,991 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	3	8/14/2020	NON-COMPETING CONTINUATION	$461,991
														Subtotal = $461,991

Issue Date FY: 2019 ( Subtotal = $457,548 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	2	8/16/2019	NON-COMPETING CONTINUATION	$457,548
														Subtotal = $457,548

Issue Date FY: 2018 ( Subtotal = $471,700 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Biology Research	000	1	8/28/2018	NEW	$471,700
														Subtotal = $471,700

Grand Total All Awards = $2,299,598

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(PQ4) Quantitative and multiplexed analysis of gene function in cancer in vivo

Award Number: R01CA231253

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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