Although many men with advanced prostate cancer initially respond to androgen ablation therapy, the development of castration resistance is nearly inevitable. Progression to castration resistance leads to disease progression and, ultimately, death from prostate cancer. Despite intensive efforts, the genetic basis for castration resistance remains incompletely characterized. Similarly, the identification of genetic features that distinguish indolent from lethal disease has proved elusive. Advances in systematic genomic and functional technologies in recent years provide an unprecedented opportunity to make new scientific inroads into these longstanding challenges. The overarching goal of this research is to leverage these advances to address two cardinal questions in prostate cancer research: 1, the genetic determinants of indolent versus aggressive disease;and 2, a systematic understanding of mechanisms of resistance to castration-based therapy. These issues will be addressed through a series of complementary approaches. First, whole genome sequencing will be performed on >80 specimens obtained from castration-resistant bone metastases, or from primary tumors resected following neoadjuvant androgen blockade. Here, the goal is to identify recurrent genomic alterations that are preferentially associated with castration resistance. Next, we will develop a targeted massively parallel sequencing approach to enable high-throughput mutational profiling of mutations and rearrangements characteristic of clinically aggressive and/or castration resistant prostate cancer. This approach will be applied to 300 prostate tumor DNAs, thus providing a robust cohort in which to validate the observations from the whole genome sequencing efforts. The targeted approach may also provide a basis for new diagnostic modalities capable of stratifying prostate cancer patients for genomics-driven clinical trials. In addition, we will perform a genome-scale ORF screen to identify mechanisms of resistance to androgen ablation. Together, these studies should provide many new insights that propel new diagnostic and therapeutic options for men with clinically aggressive and castration-resistant prostate cancer.

Public Health Relevance

Two of the most important unmet medical needs in prostate cancer are the ability to distinguish indolent from aggressive disease and ascertaining how these tumors become resistant to castration-based therapy. Upon completion of this project, we expect to have identified new, clinically relevant determinants of aggressive disease and resistance to androgen ablation. This knowledge may help improve the diagnosis and treatment of many men with advanced prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA090381-12
Application #
8764823
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02215
Preston, Mark A; Batista, Julie L; Wilson, Kathryn M et al. (2016) Baseline Prostate-Specific Antigen Levels in Midlife Predict Lethal Prostate Cancer. J Clin Oncol 34:2705-11
Sinnott, Jennifer A; Peisch, Sam; Tyekucheva, Svitlana et al. (2016) Prognostic Utility of a New mRNA Expression Signature of Gleason Score. Clin Cancer Res :
Yang, Meng; Zu, Ke; Mucci, Lorelei A et al. (2016) Vascular morphology differentiates prostate cancer mortality risk among men with higher Gleason grade. Cancer Causes Control 27:1043-7
Thorgeirsson, Tryggvi; Jordahl, Kristina M; Flavin, Richard et al. (2016) Intracellular location of BRCA2 protein expression and prostate cancer progression in the Swedish Watchful Waiting Cohort. Carcinogenesis 37:262-8
Kelly, Rachel S; Vander Heiden, Matthew G; Giovannucci, Edward et al. (2016) Metabolomic Biomarkers of Prostate Cancer: Prediction, Diagnosis, Progression, Prognosis, and Recurrence. Cancer Epidemiol Biomarkers Prev 25:887-906
Gerrin, Sean J; Sowalsky, Adam G; Balk, Steven P et al. (2016) Mutation Profiling Indicates High Grade Prostatic Intraepithelial Neoplasia as Distant Precursors of Adjacent Invasive Prostatic Adenocarcinoma. Prostate 76:1227-36
Liu, Xiaming; Han, Weiwei; Gulla, Sarah et al. (2016) Protein phosphatase 1 suppresses androgen receptor ubiquitylation and degradation. Oncotarget 7:1754-64
Ahearn, Thomas U; Tchrakian, Nairi; Wilson, Kathryn M et al. (2016) Calcium-Sensing Receptor Tumor Expression and Lethal Prostate Cancer Progression. J Clin Endocrinol Metab 101:2520-7
Li, Zhenfei; Alyamani, Mohammad; Li, Jianneng et al. (2016) Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy. Nature 533:547-51
Xie, Wanling; Yang, Ming; Chan, June et al. (2016) Association of genetic variations of selenoprotein genes, plasma selenium levels, and prostate cancer aggressiveness at diagnosis. Prostate 76:691-9

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