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Targeting Genomic Instability in Lethal Neuroendocrine Prostate Cancer

Award Number: R01CA222877
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/06/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Targeting Genomic Instability in Lethal Neuroendocrine Prostate Cancer - PROJECT SUMMARY There is a crucial clinical need to identify therapeutic targets for patients with highly aggressive and lethal prostate cancer. While chromosome instability has long been recognized as a marker of advanced prostate cancer, our understanding of the mechanisms that induce disrupted cancer genomes (aneuploidy and DNA copy number alterations) and how they contribute to aggressive phenotypes is limited. Recent large cohort studies have revealed highly recurrent DNA copy number alterations (CNA) in prostate and other cancers – but the section forces behind this conserved evolution of the cancer genome are not completely understood. In prostate cancer, there is a wide spectrum of outcomes and of genomic instability associated aneuploidy. Organ confined, better prognosis cases of prostate cancer are typically diploid; while therapy-resistant, poor outcome cases are highly aneuploid. Improved androgen-targeted prostate therapies (e.g. enzalutamide and abiraterone) impact quality of life, but tumors frequently escape therapy through mechanisms involving transdifferentiation to the nueroendocrine prostate cancer (NEPC) subtype. NEPC is highly aggressive, and thus there is a vital need to better understand the biology and therapeutic vulnerabilities of this subtype. The contribution of DNA copy number alterations to driving aggressive cancer phenotypes is insufficiently understood. Here we propose a systematic study to use integrated omics to identify genes and mutations associated with chromosome instability and test their roles in an experimental model of NEPC prostate cancer. Our project is centered on the hypothesis that in sum, activating oncogene mutations, tumor suppressor gene loss, and more subtle but accumulative coordinate changes in CNA patterns are each contributing to aggressive cancer phenotypes. We will use our prostate transformation model to test this hypothesis by altering the balance between strong oncogene contributions and CNA-based contributions, enabled by genomic instability, and testing the aggressive phenotypes of the resulting tumors. We anticipate that by increasing the role of genomic instability, we will develop model systems that more closely resemble the human disease. We will thus use our model as a pre-clinical testing ground for determining if the genes promoting or enabling genomic instability are Achilles’ heels that can be therapeutically targeted. Our project is part of a newer movement to expand the molecular classification of tumors to include the underlying mechanisms of genomic instability, and to understand how linkage-constrained refinement of the genome can contribute to aggressive tumor phenotypes. The complexity of how tumor evolution optimizes linkage-constrained copy number changes is a robust fit to a systems biology approach. Our project will leverage the cancer biology and modeling expertise of the Witte lab with the cancer systems biology expertise of the Graeber lab.


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 = -$2,275 )
2024	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	5	2/2/2024	NON-COMPETING CONTINUATION	-$2,275
														Subtotal = -$2,275

Issue Date FY: 2022 ( Subtotal = $519,628 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	5	8/1/2022	NON-COMPETING CONTINUATION	$519,628
														Subtotal = $519,628

Issue Date FY: 2021 ( Subtotal = $530,232 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	4	5/13/2021	NON-COMPETING CONTINUATION	$530,232
														Subtotal = $530,232

Issue Date FY: 2020 ( Subtotal = $530,232 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	3	4/30/2020	NON-COMPETING CONTINUATION	$530,232
														Subtotal = $530,232

Issue Date FY: 2019 ( Subtotal = $514,324 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	2	5/17/2019	NON-COMPETING CONTINUATION	$514,324
														Subtotal = $514,324

Issue Date FY: 2018 ( Subtotal = $529,948 )
2018	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	1	6/6/2018	NEW	$529,948
														Subtotal = $529,948

Grand Total All Awards = $2,622,089

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Targeting Genomic Instability in Lethal Neuroendocrine Prostate Cancer

Award Number: R01CA222877

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/06/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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