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Impact of Genetic Diversity on Human Xenograft Tumor Growth

Award Number: R33CA247669
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Impact of Genetic Diversity on Human Xenograft Tumor Growth - PROJECT SUMMARY/ABSTRACT Patient derived xenograft (PDX) mouse models are an essential tool for the study of cancer biology, biomarker development, drug screening, and the preclinical evaluation of personalized medicine strategies for many types of cancers. However, xenograft failure rates due to host rejection, even in immunocompromised hosts, is between ~20% and 100% depending on tumor type. Such failure often results in a lost sample and a lost opportunity to obtain clinically relevant data for that patient or tumor type. Emerging evidence suggests that host genetic background underlies much of this variability in xenograft establishment as well as tumor response to drugs. To advance the clinical relevance of the PDX model system, an innovative alternative is to utilize genetic diversity of the host PDX mice as a tool to substantially improve tumor engraftment. The Collaborative Cross (CC) and Diversity Outbred (DO) are complementary sets of recombinant inbred and strains, respectively, that derive from eight parental inbred strains, and combine high genetic diversity with balanced population structures ideal for genetic trait mapping. The CC inbred strains provide a high degree of genetic variability and potentially a genetically tractable platform for sustained and reproducible in vivo PDX studies. DO provides the most genetic variability in outbred genomes with high levels of heterozygosity similar to the human population, and is ideal for characterizing the full range of potential effects of host genetic background variation on tumor cell expansion. To establish a PDX mouse, the host immune system must be suppressed for xenograft acceptance. The challenge in the proposed studies is to suppress the immune system in individual immunocompetent mice with different genetic backgrounds. In Aim 1, the immune system will be suppressed in CC mice by knocking out the Rag1 gene using a novel CRISPR-Cas9 base editing system. In Aim 2, the immune system will be suppressed in genetically unique DO mice using a novel oral immunosuppressant drug. This study is significant because it will provide the genetic diversity necessary for the growth of any type of tumor, expanding the PDX platform to sustain cancers that have previously been impossible to xenograft. This study is conceptually innovative because it will introduce genetic diversity into the PDX platform. This study is technically innovative because it will compromise the immune system in multiple genetically diverse mice by state-of-the-art CRISPR-Cas9 Base Editor technology (Aim 1) or using a novel chemical immunosuppressant in the drinking water (Aim 2). The state-of-the-art Base Editor system in Aim 1 will produce identical mutations in all mice with little or no collateral genetic alterations. Development of these novel platforms has risks that will be rewarded with the generation of PDX engraftment of “difficult” tumors, enabling a greater understanding of cancer biology and development of novel therapeutics. .


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: 2024 ( Subtotal = $0 )
2024	2022	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Detection and Diagnosis Research	000	3	2/1/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $414,834 )
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Detection and Diagnosis Research	000	3	8/5/2022	NON-COMPETING CONTINUATION	$414,834
														Subtotal = $414,834

Issue Date FY: 2021 ( Subtotal = $423,300 )
2021	2021	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Detection and Diagnosis Research	000	2	5/31/2021	NON-COMPETING CONTINUATION	$423,300
														Subtotal = $423,300

Issue Date FY: 2020 ( Subtotal = $423,298 )
2020	2020	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Detection and Diagnosis Research	000	1	5/20/2020	NEW	$423,298
														Subtotal = $423,298

Grand Total All Awards = $1,261,432

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Impact of Genetic Diversity on Human Xenograft Tumor Growth

Award Number: R33CA247669

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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