Research Projects

The current Michigan SPORE consists of three projects:

• Project 1: Targeting mCRPC Patients with Biallelic Loss of CDK12 (see below)
• Project 2: Integrating a Novel MiPS-Based Next- Generation Sequencing Urine Assay for the Early Detection of Unfavorable Risk PCa
• Project 3: Exploring Ablation of the Androgen Receptor as a Therapeutic Approach for mCRPC

Project 1: Targeting Metastatic Prostate Cancer Patients with Biallelic Loss of CDK12

Project Co-Leaders:
Arul Chinnaiyan, M.D., Ph.D. (Basic Leader); [email protected]
Ajjai Alva, M.D. (Clinical Co-Leader): [email protected]
Felix Feng, M.D. (Clinical Co-Leader): [email protected]

With the wide-spread integration of next-generation sequencing technology over the past several years, comprehensive genomic studies have shown that prostate cancers can be classified into different molecular subtypes. Identification of these subtypes and molecular drivers of pathogenesis represents an opportunity to design rational precision oncology approaches for treatment. To this end, we have recently identified and characterized a novel molecular subtype of prostate cancer typified by biallelic inactivation of CDK12 and shown that it is enriched in cases of metastatic castration-resistant prostate cancer (mCRPC). CDK12-mutant prostate cancers exhibit a distinct genomic instability pattern from other prostate cancer subtypes, including homologous recombination and mismatch repair-deficient, that is associated with a focal tandem duplication (FTD) phenotype. Importantly, CDK12-FTDs lead to an elevated neoantigen burden from increased gene fusions, and this is mirrored by an active immune response and increased T cell trafficking in the tumor microenvironment. Accordingly, preliminary results from mCRPC patients in our cohort suggest that they may have a higher likelihood of response to immune checkpoint blockade. We, therefore, hypothesize that inactivation of CDK12 results in an immunogenic class of mCRPC that may benefit from immune-directed therapies.

This hypothesis will be explored through the following Specific Aims:

Aim 1: Define the functional relevance of CDK12 loss to prostate cancer biology and identify synthetic lethal targets. Experiments in this Aim will focus on in vitro methods, bioinformatics analyses, and a CRISPR screen to examine how CDK12 loss impacts prostate cancer pathogenesis and drives the emergence of an immunogenomic phenotype.

Aim 2: Determine the impact of Cdk12 ablation on prostate tumor growth and immune response in vivo. We will generate several Cdk12-null mouse prostate models to directly evaluate the role of Cdk12 in prostate tumorigenesis and response to immune checkpoint blockade.

Aim 3: Identify molecular determinants of response in the first clinical trials of immune checkpoint blockade for CDK12-mutant mCPRC patients. Using samples from our Phase II trial (IMPACT) of nivolumab and ipilimumab in CDK12-mutant patients, we will analyze changes in the immune response and determine tumor-intrinsic biomarkers of response.

Project 2: Integrating a Novel MiPS-Based Next-Generation Sequencing Urine Assay for the Early Detection of Unfavorable Risk Prostate Cancer

Project Co-Leaders:
Ganesh Palapattu, M.D., F.A.C.S. (Clinical Co-Leader): [email protected]
Simpa Salami, M.D., M.P.H. (Clinical Co-Leader): [email protected]
Todd Morgan, M.D. (Clinical Co-Leader): [email protected]
Scott Tomlins, M.D., Ph.D. (Basic Leader): [email protected]

Project 2 of the Michigan Prostate SPORE seeks to improve the early detection of unfavorable risk prostate cancer by employing a novel urine-based next generation sequencing (NGS) assay. Recent studies have demonstrated that men with certain germline genetic alterations (e.g., BRCA 1/2 and Lynch syndrome) may be at increased risk of potentially aggressive prostate cancer. Men at increased genetic risk represent a newly recognized group in whom early detection is particularly compelling. Generally speaking, a central problem inherent to prostate cancer screening is the profound over diagnosis of favorable risk disease. To counterbalance the over treatment of favorable risk (i.e., Gleason 6) prostate cancer, a number of active surveillance strategies have been introduced. Transition to treatment (e.g., surgery or radiation) can be triggered by evidence of risk reclassification often due to grade progression. Improved early detection of grade progression in men with previously diagnosed favorable risk prostate cancer on active surveillance represents a major opportunity to improve treatment allocation. How to reliably identify potentially aggressive prostate cancer so treatment can be appropriately recommended continues to represent a critical knowledge gap. Building on prior work from a successful SPORE project involving the Michigan Prostate Score (MiPS) test (using transcription-mediated amplification quantification of urine KLK3, PCA3 and T2:ERG) in the previous funding cycle, we have developed an advanced novel urine-based targeted NGS assay (MIPS-NGS) to detect Gleason ≥ 7 (unfavorable risk) prostate cancer. MIPS-NGS is a targeted RNAseq assay comprised of 83 prostate cancer-specific transcripts (e.g., lncRNAs, ETS genes fusions, SPOP), several of which are aggressive prostate cancer-specific. We hypothesize that MIPS-NGS can enable the early detection of unfavorable risk prostate cancer.

To test this hypothesis, we propose the following Specific Aims:

Project 3: Exploring Ablation of the Androgen Receptor as a Therapeutic Approach for Castration-Resistant Prostate Cancer

Project Co-Leaders:
Shaomeng Wang, Ph.D. (Basic Leader): [email protected]
Ajjia Alva, M.D. (Clinical Leader): [email protected]

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.
• Aim 2: Develop potent, orally bioavailable AR degraders and study their mechanism of action.
• Aim 3: Evaluate AR degraders in preclinical models of prostate cancer to select a candidate for a Phase I clinical trial in mCRPC.