SPORE in Prostate Cancer
Sloan Kettering Institute for Cancer Research
Principal Investigator(s):
Howard I. Scher, MD
Yu Chen, MD, PhD
- Principal Investigator(s) Contact Information
- Overview
- Project 1: Genomic Predictors of Clinical Outcomes and Response to Targeted Therapy in Advanced Prostate Cancer
- Project 2: Overcoming Microenvironment-Mediated Resistance to AR Pathway Inhibition in High-Risk Prostate Cancer
- Project 3: Therapeutic Targeting of Lineage Plasticity in Castration-Resistant Prostate Cancer Biostatistics Core
- Administrative Core
- Biospecimen Repository Core
- Biostatistics & Bioinformatics Core
- Preclinical Models Core
- Biomarkers Core
- Developmental Research Program
- Career Enhancement Program
Principal Investigators Contact Information
Howard I. Scher, MD
Co-Chair, Center for Mechanism-Based Therapy
Sloan Kettering Institute for Cancer Research
1275 York Avenue
New York, NY 10021
Tel: 646-422-4327
Yu Chen, MD, PhD
Associate Attending Physician
Sloan Kettering Institute for Cancer Research
1275 York Avenue
New York, NY 10021
Tel: 646-888-2139
Overview
Over the past 20 years, the SPORE in Prostate Cancer at Memorial Sloan Kettering Cancer Center (MSK) has made significant advances in prostate cancer research and treatment, using the evolving mechanistic understanding of the drivers of tumor growth to improve patient management across the clinical spectrum. Applying a biomarker-based, risk-adapted approach, our work has led to the development of new diagnostic blood tests and prognostic models to distinguish indolent from clinically significant cancers, the discovery of new therapeutic targets, their validation in preclinical models, and the development of drugs directed to them in trials designed according to the recommendations of the Prostate Cancer Working Group 3. Our efforts have impacted clinical practice worldwide.
The overall objectives of the SPORE in Prostate Cancer at MSK are: 1) to interrogate the genomics and molecular pathways relevant to prostate cancer progression, 2) to identify and validate clinically relevant biomarkers, and 3) to develop novel agents and therapeutic strategies. In the next 5 years, we propose 3 research projects to address new clinical challenges that have emerged in the context of the evolving landscape of prostate cancer. For localized disease, the challenges are to identify patients at high risk for metastasis and death and to determine optimal upfront treatment. To address this, RP-1 will determine germline and somatic genomic features associated with disease progression in high-risk localized disease and RP-2 will determine the role of signaling from the prostate microenvironment in resistance to androgen receptor-targeted therapy and determine the efficacy of targeting these signals. For patients with metastatic disease, the widespread adoption of potent next-generation androgen receptor (AR) signaling inhibitors has changed the landscape of prostate cancer, highlighting the need for therapeutic strategies for cancers that develop AR independence. Previously our SPORE characterized the AR-independent “lineage plasticity” disease state as driven by TP53 and RB1 loss. RP-3 seeks to better define the genomic heterogeneity inherent in this disease state and evaluate novel therapeutic strategies. RP-1 will also define the genomic context that predicts for PARP inhibitor response.
Project 1: Genomic Predictors of Clinical Outcomes and Response to Targeted Therapy in Advanced Prostate Cancer
Project Co-Leaders:
David B. Solit, MD (Basic Co-Leader)
Wassim Abida, MD, PhD (Clinical Co-Leader)
Clinical sequencing has only recently begun to inform the selection of FDA-approved therapies for individual patients with prostate cancer. Among patients with BRCA and other DNA repair pathway gene mutations, only a subset—half at best—respond to approved targeted therapies. In this project, we will leverage an institutional-scale prospective tumor and germline sequencing initiative to expand our understanding of the impact of genomic alterations on clinical outcomes and response to targeted and immune-based therapies in men with prostate cancer. Our aims are to identify genomic alterations associated with progression to the lethal metastatic phenotype and to refine molecularly targeted approaches to the treatment of locally advanced and metastatic prostate cancer.
We will accomplish these translational objectivesthrough three broad approaches:
1) We will develop the largest clinical genomic data set of men with high-risk, localized prostate cancer and test the association of genomic alterations with clinical outcomes in this disease state. With a recurrence rate of at least 40%, high-risk, clinically localized prostate cancer represents an area of significant unmet need for novel treatment approaches, including the introduction of targeted therapies and molecularly guided treatment intensification to reduce the risk of recurrence.
2) We will identify molecular features of tumors with DNA damage repair (DDR) alterations that are more predictive of sensitivity or resistance to PARP inhibitors than DDR mutational status alone. We will use targeted and whole-genome sequencing analyses to explore the associations between mutational zygosity, clonality, and the presence of structural variant signatures and response to PARP inhibitor therapy.
3) We will determine the timing at which actionable DNA repair alterations arise during prostate cancer disease progression and the impact of preexisting, intrapatient heterogeneity on response to approved targeted and immunotherapies using sequential tumor and plasma sequencing.
Project 2: Overcoming Microenvironment-Mediated Resistance to AR Pathway Inhibition in High-Risk Prostate Cancer
Project Co-Leaders:
Brett Carver, MD (Basic Co-Leader)
Yu Chen, MD, PhD (Basic Co-Leader)
Dana Rathkopf, MD (Clinical Co-Leader)
Androgen blockade forms a main pillar of prostate cancer treatment, but even potent second-generation androgen receptor signaling inhibitors are only effective for a limited time, with most cancers ultimately progressing. There is a significant need to further define the mechanisms driving resistance to androgen receptor (AR)-targeted therapies in this unique context and to develop therapeutic strategies that enhance response rates in patients with high-risk localized prostate cancer to shift the treatment paradigm from disease control to cure.
We recently discovered a cellular growth factor, neuregulin 1 (NRG1), secreted by the local prostate cancer microenvironment, that promotes the survival of prostate cancer cells under conditions of androgen blockade. Parallel studies in prostate cancer preclinical models revealed that stromal-derived NRG1 in the prostate cancer microenvironment promotes cancer cell persistence following AR-targeted therapies. Secreted NRG1 promotes resistance through HER2/3-PI3K/AKT-mediated signaling in prostate cancer epithelial cells. We are now poised to define the NRG1 downstream signaling nodes driving cancer cell persistence in the face of AR-targeted therapies and optimize therapeutic strategies targeting the NRG1 axis in combination with AR inhibition. In this project, we will investigate the effects of targeting individual nodes of the NRG1-HER2/3-PI3K pathway to overcome resistance to AR-targeted therapies in preclinical trials using clinical-grade inhibitors of NRG1, HER2/3, PI3K, and AKT in combination with AR antagonists. We will also take a comprehensive approach to defining the microenvironmental mechanisms contributing to prostate cancer cell persistence after AR-targeted therapy. Using single-cell sequencing technology, we will define the changes in prostate cancer microenvironmental cell populations following AR inhibition and evaluate differential gene expression within these cell populations to identify novel cytokine-receptor pairs contributing to cancer cell persistence in primary and metastatic prostate cancers. Finally, we will conduct a phase Ib/II neoadjuvant clinical trial of a PI3K inhibitor (copanlisib) and androgen-deprivation therapy prior to prostatectomy in patients harboring loss of PTEN, an established mediator of resistance to AR-targeted therapies.
Project 3: Therapeutic Targeting of Lineage Plasticity in Castration-Resistant Prostate Cancer
Project Co-Leaders:
Charles Sawyers, MD (Basic Co-Leader)
Howard Scher, MD (Clinical Co-Leader)
The clinical success of androgen receptor (AR)—signaling inhibitors such as abiraterone and enzalutamide has significantly extended survival for men with castration-resistant prostate cancer (CRPC), but metastatic CRPC tumors acquire resistance to these agents through a variety of mechanisms. Recent genomics studies have shown that men with CRPC harbor an unexpectedly high frequency of alterations in the tumor suppressor genes TP53 and RB. In laboratory studies, we have found that these alterations lead tumor cells to change their identity and thereby become resistant to anticancer therapies that target the androgen receptor. Of particular concern, due to increased aggressiveness and lethality, is the development of lineage plasticity: when the tumor transitions from a classical, AR-positive, prostate-specific antigen (PSA)-expressing adenocarcinoma to an AR-low/negative, PSA-low tumor with undifferentiated or neuroendocrine/small cell histology.
In this project, we will characterize these altered tumor cells through single-cell analysis; evaluate four inhibitory therapies that may delay, prevent, or even reverse the changes that cause resistance; and develop blood-based biomarkers that can be incorporated into clinical trials to predict and monitor patient response to these types of therapies. We will be investigating inhibitors of JAK kinases, FGFR, EZH2, and p300/CBP in preclinical models using patient-derived organoids and xenografts in order to understand these agents’ activity against CRPC that has developed lineage plasticity. We aim to address diagnostic challenges by evaluating these markers in blood-based assays such as circulating tumor cells (CTCs) and cell-free tumor DNA (cfDNA). To that end, we will evaluate the frequency of DLL3 expression and additional CTC/cfDNA biomarkers representing therapeutic targets and investigate morphologic, phenotypic, and genomic heterogeneity within biomarker-positive CTC sub-populations. Finally, we will investigate whether persistent CTC subpopulations can be utilized to provide an early indication of response, identify potential resistance mechanisms, and guide future therapeutic development.
Administrative Core
Core Directors:
Howard Scher, MD
Yu Chen, MD, PhD
The purpose of the Administrative Core is to support the translational research objectives of our SPORE in Prostate Cancer by serving as the organizational hub, optimizing collaboration among SPORE investigators within and outside Memorial Sloan Kettering Cancer Center. The services centralized in the Administrative Core provide the administrative and communications infrastructure that serves all components of the SPORE, including the research projects, the other cores, and the developmental and career enhancement programs.
Specific Aim 1: Provide coordination for all scientific and educational activities of the SPORE
Specific Aim 2: Provide centralized administrative support of day-to-day activities to all the components of the SPORE: research projects, cores, and developmental research and career enhancement programs.
Biospecimen Repository Core
Core Directors:
Anuradha Gopalan, MD
Victor Reuter, MD
The Biospecimen Repository Core is designed to provide support to the basic translational research efforts of the SPORE. The Core will continue to play a central role in collecting, annotating, storing, distributing, and tracking prostate cancer tissue and blood biospecimens from patients enrolled in research protocols. Detailed biospecimen annotation, including documentation of pre-analytic processing variables, pathology findings, and patient clinical history information will be recorded in robust relational databases. We will conduct rigorous data quality assurance and quality control measures, and standardized longitudinal follow-up of all consented patients with materials in the prostate biospecimen repository. The Core will provide SPORE investigators with expert histopathological evaluation of tumor samples both from patients enrolled on research protocols and from xenograft models.
Biostatistics & Bioinformatics Core
Core Directors:
Mithat Gonen, PhD
Nikolaus Schultz, PhD
The role of the Biostatistics & Bioinformatics Core is to support investigators of the SPORE in Prostate Cancer at Memorial Sloan Kettering Cancer Center in their research efforts, including laboratory experiments, the design and analysis of clinical trials, and bioinformatics analyses. For preclinical studies, core members will assist in the formulation of the experimental design and in the analysis and interpretation of the data at the conclusion of the studies. A core member will conduct a protocol review with SPORE investigators during the clinical trial design phase. Based on this review, we will provide a statistical section for the protocol, outlining major scientific objectives, population to be studied, primary and secondary endpoints, experimental design, a randomization procedure if necessary, analysis plans, and a targeted sample size justified in probabilistic terms. At the conclusion of the trial, data analyses will be performed to assess outcomes of the primary and secondary endpoints stated in the protocol. A similar strategy will be employed for genomic analyses and core members will be integrated within the individual studies early on, remain involved, and carry full responsibility for all quantitative aspects.
Preclinical Models Core
Core Directors:
Yu Chen, MD, PhD
Brett Carver, MD
The overall purpose of the Preclinical Models Core is to facilitate the accomplishment of the translational research goals and objectives of the SPORE by providing investigators with a biobank of state-of-the-art patient-derived and genetically engineered mouse models (GEMMs) of prostate cancer. These models currently include 23 patient-derived organoid (PDO) lines and 14 patient-derived xenograft (PDX) lines, as well as GEMMs of genetic alterations studied in the SPORE projects and organoids derived from these models. In addition, the Preclinical Models Core will provide assistance in the design and generation of transgenic and knockout/knockin mouse strains and will serve as a centralized repository for these mouse strains and materials of common interest, such as dissected tissues, DNA, RNA, and protein extracts from these strains.
Biomarkers Core
Core Directors:
Howard Scher, MD
Michael Morris, MD
The purpose of the Biomarkers Core is to provide an organizational model to accelerate the development and approval of biomarker tests that link biology to clinical outcomes within SPORE projects and across other Cores. This Core is focused on credentialing both imaging-based and liquid non-invasive assays to assess and monitor disease status by characterizing the molecular and cellular features of a cancer as it changes over time. The process of consent, patient registration, and specimen collection is undertaken in clinic, under the leadership of the Biomarkers Core. Applied to the clinic, the Biomarkers Core efforts cover patients across the prostate cancer disease continuum. The Biomarkers Core will also conduct under its leadership the three imaging protocols, for FDHT, PSMA, and DLL3 PET. This core complements the other SPORE cores and MSK resources that include the Center for Molecular Oncology (CMO), Sloan Kettering Institute (SKI), the Human Oncology and Pathogenesis Program (HOPP), Clinical Laboratories, the Early Drug Development (EDD) Service, and other clinical services. Priorities for the Core are determined by unmet needs in basic research, drug development, and clinical practice, with the objective of enabling more informed diagnostic and therapeutic decisions so that patient outcomes are improved.
Developmental Research Program
Program Directors:
Howard Scher, MD
Yu Chen, MD, PhD
Charles L. Sawyers, MD
Michael J. Morris, MD
The purpose of the Developmental Research Program (DRP) of the MSK SPORE in Prostate Cancer is to support innovative translational research projects in prostate cancer. This program will allow us to respond quickly to new opportunities in translational research. Through the DRP, we will provide seed funding for innovative, investigator-initiated research in the etiology, prevention, diagnosis, and treatment of prostate cancer; fund research with exceptional potential to advance the translational research goals of the SPORE with timely response to new research opportunities; and establish a mechanism for strategic interactions with other SPOREs and other major national and international research centers.
Career Enhancement Program
Program Directors:
James Eastham, MD
Dana E. Rathkopf, MD
The SPORE Career Enhancement Program (CEP) prepares physicians and scientists for independent careers as investigators in translational research in prostate cancer. We have designed the CEP to form both an interdepartmental and an interinstitutional training ground to produce investigators who will become intellectual leaders in their fields of interest. By combining the research and academic resources available throughout Memorial Sloan Kettering Cancer Center and at our affiliated institutions, we have a long tradition of successful faculty development. Recruiting and/or developing the career of junior faculty members committed to translational research in prostate cancer is a centerpiece of our program. Over the next 5 years we will continue to recruit and develop the careers of junior faculty members and experienced investigators—from both basic research and clinical backgrounds—committed to translational research in prostate cancer.