For metastatic castration resistant prostate cancer, recent advances have led to the deployment of """"""""second- generation"""""""" ADT (ADT2) therapies, including abiraterone acetate (AA), which targets a component of androgen biosynthesis, and enzalutamide, which targets the androgen receptor directly. Both AA and enzalutamide have demonstrated an overall survival benefit in patients with metastatic CRPC;however, most patients still develop resistance to these agents, which drives prostate cancer-associated morbidity and mortality. Several mechanisms of resistance to ADT2 have recently been identified, although the overall spectrum of resistance mechanisms to ADT2 remains incompletely characterized, as does the biological impact of these events. Moreover, the extent to which such mechanisms might generalize across ADT2 regimens or operate in specific therapeutic contexts remains unknown. Finally, subsequent treatment options for this patient population beyond the use of cytotoxic chemotherapies (e.g. taxanes) are not well defined. The goal of this proposal is to create and apply computational biology algorithms that 1) systematically interrogate genomic resistance effectors to ADT2 in clinically relevant time points, 2) integrate in vitro models of ADT2 resistance with genomic features to define biological modules germane to ADT2 resistance, and 3) model clinical resistance with genomic data to inform subsequent treatment strategies. In doing so, we aim to discover new modules for clinical ADT2 resistance, provide insight into the expansion of rational treatment approaches for ADT2-resistant patients, and create an inferential framework through which clinicians may ultimately predict those treatment strategies most likely to benefit individual patients based on tumor genomic profiles. These efforts will facilitate a focused and comprehensive assessment of ADT2 resistance in the neoadjuvant and metastatic CRPC settings, explain genetic resistance to ADT2 in prostate cancer, and define subsequent therapeutic strategies.

Public Health Relevance

Emerging therapies have improved clinical outcomes for patients with metastatic prostate cancer, although most patients develop resistance to these agents and cannot be cured. Resistance mechanisms may be driven by genetic changes in the tumors of these patients, which may be targetable with other therapies. This project aims to dissect clinical resistance to these agents and determine subsequent treatment approaches for this large patient population.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lim, Susan E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dana-Farber Cancer Institute
United States
Zip Code
AlDubayan, Saud H; Giannakis, Marios; Moore, Nathanael D et al. (2018) Inherited DNA-Repair Defects in Colorectal Cancer. Am J Hum Genet 102:401-414
Viswanathan, Srinivas R; Ha, Gavin; Hoff, Andreas M et al. (2018) Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing. Cell 174:433-447.e19
Armenia, Joshua; Wankowicz, Stephanie A M; Liu, David et al. (2018) The long tail of oncogenic drivers in prostate cancer. Nat Genet 50:645-651
Miao, Diana; Margolis, Claire A; Vokes, Natalie I et al. (2018) Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors. Nat Genet 50:1271-1281
Nava Rodrigues, Daniel; Rescigno, Pasquale; Liu, David et al. (2018) Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. J Clin Invest 128:4441-4453
Miao, Diana; Margolis, Claire A; Gao, Wenhua et al. (2018) Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science 359:801-806
Liu, David; Abbosh, Philip; Keliher, Daniel et al. (2017) Mutational patterns in chemotherapy resistant muscle-invasive bladder cancer. Nat Commun 8:2193
Gibson, William J; Ruan, Daniel T; Paulson, Vera A et al. (2017) Genomic Heterogeneity and Exceptional Response to Dual Pathway Inhibition in Anaplastic Thyroid Cancer. Clin Cancer Res 23:2367-2373
George, Suzanne; Miao, Diana; Demetri, George D et al. (2017) Loss of PTEN Is Associated with Resistance to Anti-PD-1 Checkpoint Blockade Therapy in Metastatic Uterine Leiomyosarcoma. Immunity 46:197-204
AACR Project GENIE Consortium (2017) AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov 7:818-831

Showing the most recent 10 out of 23 publications