The past decade has brought the approval of several new treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) that extend overall survival. However, there is no cure for mCRPC, and development of novel therapeutic strategies is critical. Abiraterone and enzalutamide are two agents targeting the androgen receptor (AR) signaling pathway that extend patient survival, confirming the notion that AR remains a driver of mCRPC despite castrate levels of androgen ligands. Several mechanisms evolve during progression to mCRPC and resistance to abiraterone/enzalutamide that function to maintain AR signaling. These include amplification of AR, mutation of the ligand-binding domain of AR, and emergence of constitutively active alternatively spliced AR variants. This suggests that methods to ablate AR expression in mCRPC and deplete continued AR signaling may be effective in providing further survival benefit to patients. In this project, we will evaluate two approaches to ablate AR in mCRPC: AR antisense oligonucleotides (ASOs) and AR degraders. The AR ASO, IONIS-AR-2.5-Rx, has cleared a Phase I study and showed promising clinical responses in a heavily pretreated mCRPC population. Importantly, IONIS-AR-2.5-Rx targets full-length, mutant, and splice variant forms of AR. We have also undertaken a major effort to develop PROTAC (PROteolysis TArgeting Chimeric) AR degraders that function by targeting AR protein to an E3 ubiquitin ligase. Together, we hypothesize that ablation of AR, through ASOs or PROTAC degraders targeting AR, is a highly attractive therapeutic approach for mCRPC, and we will test this through the following Specific Aims:
Aim 1 : Evaluate IONIS-AR-2.5Rx, a next-generation AR ASO, in combination with enzalutamide in a Phase Ib/II clinical trial for the treatment of mCRPC. Here, we will continue the clinical development of IONIS-AR-2.5-Rx by performing a trial (ARRO-CITO) in combination with enzalutamide in chemotherapy-nave mCRPC patients. Molecular biomarkers of response will be identified through integrative clinical sequencing of tumors from the trial.
This Aim will provide clinical proof-of-concept for AR ablative strategies in mCRPC.
Aim 2 : Develop potent, orally bioavailable AR degraders and study their mechanism of action. As a second approach to deplete AR levels, we will develop a PROTAC AR degrader through a stepwise drug development process and confirm its mechanism of action in vitro.
Aim 3 : Evaluate AR degraders in preclinical models of prostate cancer to select a candidate for a Phase I clinical trial in mCRPC. We will perform in vivo experiments in the first part of this Aim to assess pharmacokinetics, pharmacodynamics, and antitumor activity of our top AR degraders. A Phase I study will then be initiated with our lead compound in mCRPC patients, representing the first advancement of an AR degrader into clinical trials. These studies will lead to the development of two therapeutic approaches to ablate AR levels in mCRPC and prevent continued signaling through this driver pathway.

Public Health Relevance

Many mechanisms evolve to maintain active androgen receptor (AR) signaling during progression to castration- resistant prostate cancer (CRPC) and following treatment with AR-targeting therapeutics, signifying the importance of this driver pathway. To target remaining AR activity in CRPC, we will develop and evaluate two complementary approaches to deplete AR: AR antisense oligonucleotides and small-molecule AR degraders. Completion of the preclinical studies and clinical trials of these two agents outlined in this proposal will credential AR ablation approaches as viable options for CRPC treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Ann Arbor
United States
Zip Code
Zhang, Yajia; Pitchiaya, Sethuramasundaram; Cie?lik, Marcin et al. (2018) Analysis of the androgen receptor-regulated lncRNA landscape identifies a role for ARLNC1 in prostate cancer progression. Nat Genet 50:814-824
Hussain, Maha; Daignault-Newton, Stephanie; Twardowski, Przemyslaw W et al. (2018) Targeting Androgen Receptor and DNA Repair in Metastatic Castration-Resistant Prostate Cancer: Results From NCI 9012. J Clin Oncol 36:991-999
Salami, Simpa S; Hovelson, Daniel H; Kaplan, Jeremy B et al. (2018) Transcriptomic heterogeneity in multifocal prostate cancer. JCI Insight 3:
Zhao, Shanshan; Leonardson, Amy; Geybels, Milan S et al. (2018) A five-CpG DNA methylation score to predict metastatic-lethal outcomes in men treated with radical prostatectomy for localized prostate cancer. Prostate :
Niknafs, Yashar S; Pandian, Balaji; Gajjar, Tilak et al. (2018) MiPanda: A Resource for Analyzing and Visualizing Next-Generation Sequencing Transcriptomics Data. Neoplasia 20:1144-1149
Xiao, Lanbo; Tien, Jean C; Vo, Josh et al. (2018) Epigenetic Reprogramming with Antisense Oligonucleotides Enhances the Effectiveness of Androgen Receptor Inhibition in Castration-Resistant Prostate Cancer. Cancer Res 78:5731-5740
Piert, Morand; Shankar, Prasad R; Montgomery, Jeffrey et al. (2018) Accuracy of tumor segmentation from multi-parametric prostate MRI and 18F-choline PET/CT for focal prostate cancer therapy applications. EJNMMI Res 8:23
Wu, Yi-Mi; Cie?lik, Marcin; Lonigro, Robert J et al. (2018) Inactivation of CDK12 Delineates a Distinct Immunogenic Class of Advanced Prostate Cancer. Cell 173:1770-1782.e14
Rice, John D; Tsodikov, Alex (2017) Semiparametric profile likelihood estimation for continuous outcomes with excess zeros in a random-threshold damage-resistance model. Stat Med 36:1924-1935
Shen, Rex; Luo, Lan; Jiang, Hui (2017) Identification of gene pairs through penalized regression subject to constraints. BMC Bioinformatics 18:466

Showing the most recent 10 out of 65 publications