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Patient-Derived Models of Prostate Cancer for Personalized Medicine

Award Number: U01CA224044
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Patient-Derived Models of Prostate Cancer for Personalized Medicine - PROJECT SUMMARY/ABSTRACT Metastatic prostate cancer (PCa) that progresses after androgen ablation therapy (i.e., castration-resistant PCa [CRPC]) remains incurable. Gaining a mechanistic understanding of PCa progression has been hampered by a lack of clinically relevant PCa models. Recently, patient-derived models of cancer (PDMCs; e.g., patient-derived xenografts [PDXs] and organoids) have been used to develop therapeutically relevant approaches. We hypothesize that longitudinal studies of tumor specimens (and corresponding PDMCs) obtained over time from the same patient will lead to a better understanding of the diverse dominant pathways that drive metastatic progression. We also hypothesize that organoids will complement PDXs as part of an integrated analysis of human tissue and derived PDMCs (obtained at single time points) to understand the mechanisms of response and resistance to target pathways commonly activated in CRPC. We will test these hypotheses through the following specific aims: Aim 1. Analyze human donor tumors and corresponding PDMCs to identify dominant molecular alterations that drive PCa progression and select models to study. We will develop PDMCs from clinically annotated tumor specimens derived from men with potentially lethal PCa, including PDMCs derived from tumor specimens obtained at different times during progression (longitudinal studies) and from different areas of the same tumor. We will assess human PCa specimens and PDMCs’ morphology and expression of genes associated with PCa progression and subject them to whole-exome sequencing and RNA sequencing. PCa specimens and PDMCs derived from the longitudinal studies will also be subjected to whole-genome sequencing and epigenomic analysis. Finally, we will develop a publicly available interactive database linking molecular and preclinical results of PDMC characterization with clinical and molecular details of donor human PCa. These studies' findings will serve as the basis for the identification and prioritization of aberrant molecular pathways for further study. This knowledge is also essential to understanding how each PDMC provides information about the alterations in human donor tumor. Aim 2. Study genomic alterations acquired in metastasis specimens in the longitudinal studies for their potential to confer metastatic ability to cells. We will genetically modify organoids to create the genomic alterations found in the metastases. We will subsequently study how the genetic modification of these genes influences specific steps involved in metastasis, namely invasion, migration, and ability to grow at distant sites. Aim 3. Utilize PDMCs to study mechanisms of PCa response/resistance to targeted therapies on pathways implicated in PCa progression. We will seek a mechanistic understanding of PCa response and/or resistance to therapies in clinical trials targeting the AR, DNA damage response, Wnt-canonical, and PI3K pathways. These studies will inform the discovery and elucidation of resistance mechanisms, the development of effective therapies and will provide insights into the roles of PDMCs as model systems for studying signaling and therapeutic response.


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 = -$47,437 )
2026	2023	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	12/10/2025	NON-COMPETING CONTINUATION	-$47,437
														Subtotal = -$47,437

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	4/26/2024	NON-COMPETING CONTINUATION	$0
2024	2023	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	5	6/12/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $1,005,497 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	9/8/2023	NON-COMPETING CONTINUATION	$1,005,497
														Subtotal = $1,005,497

Issue Date FY: 2022 ( Subtotal = $1,005,497 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	4	8/12/2022	NON-COMPETING CONTINUATION	$1,005,497
2022	2021	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	5/10/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,005,497

Issue Date FY: 2021 ( Subtotal = $1,026,019 )
2021	2021	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	3	8/20/2021	NON-COMPETING CONTINUATION	$1,026,019
2021	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	2	3/8/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,026,019

Issue Date FY: 2020 ( Subtotal = $1,051,939 )
2020	2020	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	2	7/17/2020	NON-COMPETING CONTINUATION	$1,051,939
														Subtotal = $1,051,939

Issue Date FY: 2019 ( Subtotal = $1,041,019 )
2019	2019	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	7/29/2019	NEW	$1,041,019
														Subtotal = $1,041,019

Grand Total All Awards = $5,082,534

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Patient-Derived Models of Prostate Cancer for Personalized Medicine

Award Number: U01CA224044

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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