Prostate Cancer SPORE Projects

Laboratory technician uses a pipette

Collaboration leads to research breakthroughs

Our three current projects are supported by ongoing institutional commitment of funding and space, successful Career Development and Developmental Research Programs, and three cores: Administrative, Biostatistics/Bioinformatics, and Biospecimen/Pathology. 

Project 1: Targeting PIKfyve-driven lipid homeostasis as a metabolic vulnerability in neuroendocrine prostate cancer

 

Neuroendocrine prostate cancer (NEPC) is an aggressive form of advanced prostate cancer with few treatment options other than systemic chemotherapies, for which patients invariably develop resistance. Targeted therapies are, thus, urgently needed for this lethal disease. Although NEPC can arise de novo, most cases result from an adenocarcinoma to neuroendocrine transdifferentiation process that occurs in tumors of castration-resistant prostate cancer (CRPC) patients receiving standard of care therapies targeting the androgen receptor (AR). The tumor microenvironment of NEPC is often hypoxic and nutrient-depleted, leading to enhanced dependence on autophagy and lysosome-dependent nutrient survival pathways within cancer cells. Blocking autophagy with genetic methods suppresses tumor growth and increases survival in preclinical models. Here, we have identified the lipid kinase PIKfyve as a key player mediating autophagy and lysosomal adaptation processes in NEPC. Interestingly, although AR-positive CRPC is sensitive to PIKfyve inhibitors in vitro, PIKfyve inhibitor treatment results in cytotoxicity in NEPC cells and enhanced tumor growth inhibition and regression. Our preliminary data also suggest that PIKfyve inhibition results in increased de novo lipid synthesis and that combined targeting of the MAPK pathway and PIKfyve may be a synthetic lethal strategy for NEPC. Here, we will develop potent, selective PIKfyve degraders and employ them to validate PIKfyve as a viable therapeutic target for NEPC. Pathways leading to enhanced activity of PIKfyve inhibition (e.g., MEK inhibition) in NEPC will also be delineated. The following specific aims will be pursued:

Aim 1: Employ novel proteolysis-targeting chimera (PROTAC) degraders to define the mechanism by which PIKfyve loss preferentially impacts NEPC.

Aim 2: Define synthetic lethality relationships with PIKfyve antagonism in NEPC. 

Aim 3: Determine whether PIKfyve degradation combined with standard of care therapies for NEPC enhances outcomes in preclinical models. 

Aim 4: Establish an investigator-initiated phase II trial evaluating a clinical PIKfyve inhibitor (ESK981) in NEPC. 

Project 2: Validation and clinical utility of a multiplex urine biomarker for identification of clinically significant prostate cancer

 

While serum prostate-specific antigen (PSA)-based screening for prostate cancer early detection reduces cancer-specific mortality, the limited specificity of PSA for clinically significant cancer (csPCa; Grade Group [GG]≥2) results in the over-detection of indolent disease, subjecting patients to the harms of overtreatment. Similarly, while unequivocal evidence has demonstrated the safety of active surveillance (AS) for favorable-risk disease, adoption has been modest. While multiparametric magnetic resonance imaging and current biomarker tests have both been utilized in the AS and initial diagnostic settings, their prognostic performance in these scenarios is mixed. Thus, there remains a critical need for a reliable, accurate biomarker for csPCa detection. Our long-term goal is to enable accurate, large-scale, non-invasive biomarker testing to reliably identify individuals with csPCa and demonstrate clinical utility of a biomarker-based approach for early detection. The objective of the current project is to evaluate, optimize, and validate a novel urine-based biomarker (MPS2) to detect csPCa. MPS2 is an 18-gene multiplex, qPCR-based assay that was externally validated in the prospective National Cancer Institute–Early Detection Research Network PCA3 Evaluation Trial. With AS now the recognized standard of care for patients with low-risk prostate cancer, the goals of both early detection and AS have merged: namely, to detect csPCa and spare others from unnecessary procedures or treatments. The absence of reliable biomarkers to identify men with csPCa among those with an elevated PSA or on AS represents a significant clinical gap. We hypothesize MPS2 will improve strategies for csPCa detection in both settings. To test this hypothesis, we propose the following aims:

Aim 1: Evaluate the clinical utility of MPS2 testing for detection of csPCa in patients with elevated PSA. 

Aim 2: Validate a urine-based molecular assay in the AS setting to identify patients likely to harbor or subsequently develop csPCa. 

Project 3: Development of serine/threonine phosphatase PP2A molecular glues for the treatment of advanced prostate cancer

 

Protein Phosphatase 2A (PP2A) functions as a tumor suppressor and is frequently inactivated in cancer by genetic and non-genetic mechanisms. PP2A biogenesis is highly regulated through predominantly non-genetic mechanisms, specifically carboxymethylation of the terminal L309 residue catalyzed by the enzyme leucine carboxy methyltransferase (LCMT1). In general, carboxymethylation of L309 is required for the formation of tumor suppressive PP2A holoenzymes, and loss of this post-translational modification is commonly seen in cancer. We recently showed that loss of PP2A carboxymethylation is a common event in prostate cancer and is associated with progression, increased metastatic potential, and treatment resistance to androgen deprivation therapies. Genetic depletion of LCMT1 results in AR and MYC activation and drives prostate cancer growth. We and others have demonstrated that, specifically, the PP2A AB56αC heterotrimer is a major negative regulator of AR and MYC signaling. We have developed a series of first-in-class PP2A molecular glues (PMGs) that stabilize the tumor suppressive PP2A AB56αC heterotrimer, resulting in inhibition of prostate cancer growth both in vitro and in vivo. The lead compound, RPT04402, has undergone extensive preclinical toxicology studies in two animal species and has entered IND-enabling studies. The goals of this project are to define the depth and breadth of activity of RPT04402 in translationally aligned xenograft and patient-derived xenograft models of metastatic castration-resistant prostate cancer (mCRPC), identify substrate/effector pathways that drive preclinical efficacy, and evaluate RPT04402 as a monotherapy and, if preclinical data warrant, in combinations (e.g., enzalutamide) through a clinical trial. 

Aim 1: Elucidate the mechanism of action of PP2A molecular glues (PMGs) in affecting AR signaling and prostate cancer growth in cell line and organoid models. 

Aim 2: Conduct comprehensive efficacy studies of RPT04402, a clinical candidate PMG, alone and in combination with AR-targeting agents employing multiple preclinical models of CRPC. 

Aim 3: Determine predictive biomarkers of response to PMGs and initiate a phase I/II trial with RPT04402 in metastatic CRPC patients.