Project 1: A Precision Medicine Approach to Elucidate Mechanisms of Progression and Resistance to Therapy in Advanced Prostate Cancer
The University of Michigan Comprehensive Cancer Center (UMCCC) has taken on a leadership role in developing precision medicine approaches for oncology. In April of 2011, the MI-ONCOSEQ clinical sequencing program was established, which prospectively enrolls patients with advanced cancers for comprehensive mutational analysis using an integrative sequencing approach. Since establishment of this protocol, over 250 adults and 40 children with cancer have been sequenced with return of results through an institutionally sanctioned "precision medicine tumor board" (PMTB). Through support of the UM Prostate SPORE, Dr. Chinnaiyan and colleagues used this approach to establish the first mutational landscape of lethal castration resistant prostate cancer (CRPC) (Nature 2012).
This Project will evaluate the mutational landscape of metastatic hormone sensitive prostate cancer (HSPC) along with CRPC, and thus, will employ precision medicine approaches for earlier stages of prostate cancer progression (i.e., prior to castration resistance). Furthermore, we will also explore mechanisms of resistance/progression in UMCCC-based clinical trials in metastatic prostate cancer as well as develop parallel in vitro "tumoroid" model systems.
Aim 2: Determine mechanisms of progression and resistance to therapy of men with metastatic CRPC. Here we will study the mutational landscape of patients with metastatic CRPC that will enroll in a targeted therapy trial to evaluate the tyrosine kinase inhibitor, cabozatanib. We will carry out integrative sequencing of the tumor specimens obtained at time of trial enrollment and at time of progression/recurrence. This will allow for one the first of its kind, temporal assessments of the mutational landscape of prostate cancer progression under targeted therapies.
Aim 3: Establish prostate tumoroid cultures as a parallel model system in the precision medicine approach. These patient derived tumoroid cultures will be used to test predictions made by integrative sequencing.
Project 2: Mechanisms of Sensitivity and Resistance to the Kinase Inhibitor Cabozantinib in Castrate Resistant Prostate Cancer
In a recent clinical trial led by Co-Leader Dr. Smith, Cabozantinib (CABO; XL-184) showed unprecedented bone scan responses in men with castration-resistant prostate cancer (CRPC). Although marked responses are seen, patients eventually progress and about 30% of patients do not respond. CABO is a multi-tyrosine kinase inhibitor with greatest activity against MET, VEGFR2 and RET, which have been implicated in prostate cancer (PCa) progression and the bone microenvironment. Using preclinical models we have found that some PCas show differential sensitivity to CABO when in bone versus soft tissue. Furthermore, through integrative sequencing, we have found that MET activation compensates for loss of androgen receptor (AR) signaling in CRPC. These clinical and pre-clinical results provide a compelling rationale for studying the role of both the tumor itself and the tumor microenvironment in predicting tumor sensitivity and resistance to CABO. Hence, the overarching goal of this proposal is to leverage an ongoing investigator-initiated clinical trial of CABO and use in vitro and in vivo modeling to "reverse-engineer" sensitivity and resistance mechanisms using a bedside to bench approach.
Aim 1. Determine if clinical response to CABO in men with CRPC is associated with inhibition of MET/VEGFR/RET signaling. Clinical response to CABO with AR, MET, VEGF and RET signaling activity in bone and soft tissue will be evaluated. A novel method of diffusion-weighted MRI to evaluate bone response will be used and flash frozen pre-treatment and on-study biopsies for interrogation in Aim 3 will be obtained.
Aim 2. Assess the role of the microenvironment in conferring sensitivity and resistance to CABO. The response to CABO in multiple prostate cancer cell lines with varied AR and MET pathway activity in the context of tissue culture, soft tissue sites and bone sites will be evaluated. Activation and targeting of CABO-sensitive pathways (MET, VEGFR, RET and downstream effectors and AR signaling) will be evaluated. Tumors will be subjected to RNA-seq analysis to identify novel predictors of sensitivity and resistance.
Aim 3: Interrogate the role of tumor genotype and phenotype in conferring sensitivity and resistance to CABO.
An integrative sequencing strategy on the pre- and on- treatment biopsies to characterize genomic and transcriptomic predictors of sensitivity and resistance to CABO will be performed. CABO-resistant cell models will be developed and subjected to integrative sequencing to identify mechanisms of acquired resistance. Candidate mediators of resistance will then be tested in appropriate in vitro and in vivo models.
Project 3: Development of Novel BET Bromodomain Inhibitors for the Treatment of Advanced Prostate Cancer
Currently, metastatic castration-resistant prostate cancer (CRPC) is invariably and unfortunately a lethal disease. The vast majority of CRPC is dependent upon and driven by androgen receptor (AR) signaling. While recent advances have resulted in the development of second generation therapeutics targeting the androgen signaling axis (e.g. enzalutamide and abiraterone), the responses to these new agents are often not durable. Thus, there is a clear and urgent need to develop completely new therapeutic approaches directed against the AR axis. Recently, our team identified a novel strategy for targeting the AR signaling axis via inhibition of bromodomain containing 4 (BRD4), a conserved member of the bromodomain and extraterminal (BET) family of transcriptional co-activators (In Revision at Nature). We discovered that AR physically interacts with BRD4, and that treatment with the BET-bromodomain inhibitor JQ1 disrupts the AR-BRD4 interaction as well as AR recruitment to target gene loci. Compared to the direct AR antagonist enzalutamide, BET bromodomain inhibitors are much more effective in inhibition of AR-mediated gene transcription, including induction of AR targets such as TMPRSS2:ERG and PSA. Significantly, JQ1 was also more effective than enzalutamide in inhibiting the growth of CRPC xenografts. Based upon our findings, we hypothesize that BET bromodomain inhibition is a promising approach for targeting the AR axis and for treating advanced prostate cancer. Our goal in this SPORE project is to develop a potent BET-bromodomain small-molecule inhibitor (BET inhibitor) with optimized in vivo properties for the treatment of advanced prostate cancer.
Aim 1: Develop a highly potent and selective BET inhibitor with optimized in vivo properties.
Aim 2: Interrogate the AR-BRD4 signaling axis with novel BET inhibitors.
Aim 3: Establish the efficacy of BET bromodomain inhibitors using in vivo and ex vivo tumor models, and develop biomarkers of response.
Upon successful completion of the Aims, we expect to nominate promising candidate(s) that could be developed further for clinical use to treat metastatic CRPC. The ultimate goal of this project is introduce BET bromodomain inhibitors as a novel therapy for CRPC based on a unique understanding of its mechanism of action.
Project 4: Developing Schlap1 and Other IncRNAs as Prostate Cancer Biomarkers in Urine
Prostate cancer is the most common non-cutaneous cancer and the second leading cause of cancer death in American men. Recent recommendations by the US Preventative Services Task Force on PSA screening highlighted the public health concerns relating to the imprecision of PSA testing and the overtreatment of prostate cancer. PSA's limited ability to discriminate cancer from benign disease leads to well over a million prostate biopsies each year in the United States. Moreover, low grade prostate cancer is often non-fatal and the excessive use of definitive therapies such as surgery has led to significant morbidity and costs. The long-term objective of this project is to develop novel panels combining the TMPRSS2:ERG fusion with long non-coding RNAs (lncRNAs) that will allow improved clinical risk assessments for prostate biopsies and active surveillance of low grade cancer.