In the previous work of this RP, we discovered that global patterns of DNA copy number alterations (CNAs) in primary tumors were strongly associated with recurrence after radical prostatectomy. In this renewal we aim to determine the value of CNAs for predicting prostate cancer metastasis and death in men managed conservatively (Aim 3). In order to do so, we need to develop technology to measure CNAs in biopsy samples (Aim 2). We also need to refine our initial model of CNAs, which was developed using biochemical recurrence as an endpoint (Aim 1). By creating a CNA model in Aim 1 and testing it on an independent population sample in Aim 3, this research project will serve as a rigorous test of our CNA hypothesis, and fulfill the SPORE's goal for investigations into population science.
In Aim 1, we will further refine and confirm our initial model of CNAs, using metastasis and death from prostate cancer as endpoints rather than recurrence. We will also test the feasibility of using formalin-fixed paraffin-embedded tissue samples rather than frozen (as used in our prior CNA research).
In Aim 2, we will develop a """"""""miniaturized"""""""" CNA assay that can be conducted on a prostate biopsy sample by (a) determining the genomic regions that carry the most prognostic impact;(b) developing a miniaturized CNA detection platform to identify those regions, and (c) evaluating the concordance of CNA data between biopsy and radical prostatectomy samples, to establish the feasibility of our new assay.
In Aim 3, we will test the assay's success in predicting patient outcomes, using tissue samples from a large cohort of men whose prostate cancer was treated conservatively, and for whom we have a median 15-year follow-up. We are aiming to produce a biomarker which could be used to supply enough information to aid in the choice of Initial treatment, and thus ultimately reduce death from prostate cancer while also reducing unnecessary treatment of prostate cancer.

Public Health Relevance

Men newly diagnosed with low-risk prostate cancer must choose between active surveillance or aggressive curative treatment. The current methods for assessing risk level (ie, Gleason grade, PSA, and clinical stage) have limited accuracy, prompting many patients to choose aggressive treatment and thus leading to overtreatment In the population. Analyzing CNA patterns in tumor samples may provide prognostic value.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA092629-14
Application #
8730085
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2014-09-01
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
14
Fiscal Year
2014
Total Cost
Indirect Cost
City
New York
State
NY
Country
United States
Zip Code
10065
Rathkopf, Dana E; Antonarakis, Emmanuel S; Shore, Neal D et al. (2017) Safety and Antitumor Activity of Apalutamide (ARN-509) in Metastatic Castration-Resistant Prostate Cancer with and without Prior Abiraterone Acetate and Prednisone. Clin Cancer Res 23:3544-3551
Vertosick, Emily A; Assel, Melissa; Vickers, Andrew J (2017) A systematic review of instrumental variable analyses using geographic region as an instrument. Cancer Epidemiol 51:49-55
Bose, Rohit; Karthaus, Wouter R; Armenia, Joshua et al. (2017) ERF mutations reveal a balance of ETS factors controlling prostate oncogenesis. Nature 546:671-675
Yang, Zhaohui; Peng, Yu-Ching; Gopalan, Anuradha et al. (2017) Stromal hedgehog signaling maintains smooth muscle and hampers micro-invasive prostate cancer. Dis Model Mech 10:39-52
O'Rourke, Kevin P; Loizou, Evangelia; Livshits, Geulah et al. (2017) Transplantation of engineered organoids enables rapid generation of metastatic mouse models of colorectal cancer. Nat Biotechnol 35:577-582
Ku, Sheng Yu; Rosario, Spencer; Wang, Yanqing et al. (2017) Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 355:78-83
Blattner, Mirjam; Liu, Deli; Robinson, Brian D et al. (2017) SPOP Mutation Drives Prostate Tumorigenesis In Vivo through Coordinate Regulation of PI3K/mTOR and AR Signaling. Cancer Cell 31:436-451
Vickers, Andrew J; Van Calster, Ben; Steyerberg, Ewout (2017) Decision Curves, Calibration, and Subgroups. J Clin Oncol 35:472-473
Hyman, David M; Smyth, Lillian M; Donoghue, Mark T A et al. (2017) AKT Inhibition in Solid Tumors With AKT1 Mutations. J Clin Oncol 35:2251-2259
Zhang, Pingzhao; Wang, Dejie; Zhao, Yu et al. (2017) Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation. Nat Med 23:1055-1062

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