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Last Updated: 09/16/19

Weill Cornell Medicine SPORE in Prostate Cancer

Weill Cornell Medicine

Principal Investigator: Massimo Loda, MD

Principal Investigator Contact Information

Massimo Loda, MD
David D. Thompson Professor and Chairman
Department of Pathology and Laboratory Medicine
Weill Cornell Medicine
1300 York Avenue, Box 69
New York, NY 10065
Phone: (212) 746-6464
Email: mloda@med.cornell.edu

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Overall Goals and Research Strategies

Prostate cancer is one of the most common cancers in the Western hemisphere, with extreme clinical and molecular heterogeneity. In 2015, over 221,800 men were diagnosed with — and 27,540 died from — prostate cancer in the United States. Our Weill Cornell Medicine (WCM) SPORE in Prostate cancer will take a novel precision medicine approach to patient care, which will align our translational research goals with the care of men across the prostate cancer spectrum. The earliest possible detection of aggressive prostate cancer will avoid less effective late-stage therapies. We will study how to improve risk assessment in men with localized prostate cancer to enable optimal treatment choices, including active surveillance (AS). Men with advanced prostate cancer, despite treatment with next generation androgen deprivation therapy (ADT), succumb to drug resistance and disease progression. We need to optimize care through novel biomarker and treatment strategies to change lethal prostate cancer to a chronic manageable disease.

The Weill Cornell Medicine SPORE is composed of four Projects focused on highly translational areas relevant to the detection and treatment of aggressive prostate cancer (PCa). Project 1 aims to validate a novel biomarker to monitor metastatic castration resistant prostate cancer (CRPC) using genomic analysis of cell free DNA (cfDNA). Project 2 explores targeting of N-Myc and EZH2-driven CRPC. Project 3 will develop biomarkers of disease progression and response, taking tumor heterogeneity into account by using samples from the SU2C/PCF CRPC500 clinical trial. Project 4 will characterize genomic instability observed in SPOP mutant PCa with the goal of developing treatment strategies. Projects 1, 2, and 4 build on first-in-class discoveries made by study co-leaders that are fostered with significant preliminary data. Project 3 builds on highly collaborative interactions with multiple SPORE groups, using state-of-the-art genomics in a clinical (CLIA) setting.

Overall, the SPORE has 4 Aims to:

Aim 1: Develop accurate biomarkers to assess the risk of PCa disease progression. Projects 1 and 3 will address novel genomic and liquid biopsy approaches to develop biomarkers of PCa disease progression and prognosis to standard of care and emerging PARP inhibition therapies. These projects will leverage the Englander Institute for Precision Medicine (WCM) and the SU2C-PCF castration resistant prostate cancer (CRPC) 500 Trial. The initial cohorts will focus on metastatic CRPC with the hope of earlier application to delay or avoid development of metastatic PCa. Successful completion of this Aim will guide us to clinical biomarker driven strategies to decrease the development, spread, and suffering from metastatic PCa.

Aim 2: Develop new therapeutic approaches for clinically localized and CRPC that are hypothesis-driven, based on newly acquired knowledge of PCa biology and genomics, and represent a paradigm shift in treatment. Projects 2, 3, and 4 will allow us to better understand key genomic drivers of PCa. Project 3 will take an unbiased whole exome and PCa specific approach to genomic drivers, taking advantage of the CRPC500 trial. Project 4 will explore the biology of SPOP mutations, homologous repair defects, and the SPOP-PCa specific response to radiation and other inhibitors of DNA repair (e.g., PARPi). Project 2 will address the novel observation that NMYC overexpression is a key driver of neuroendocrine PCa (NEPC) associated with epigenetic alterations of EZH2. EZH2i trials for CRPC will be embedded into this project. Successful completion of this Aim will allow us to better understand SPOP and NMYC PCa and develop Precision Medicine treatment strategies in this clinical setting.

Aim 3: Leverage existing and expand new infrastructure for the successful translation of pre-clinical studies into the clinic. Building on an existing WCM infrastructure, our SPORE will expand resources and interconnectivity to maximize its translational research potential. SPORE Administrative, Biospecimen-Pathology, and Computational-Biostatistical Cores will be paramount to our success. We will leverage institutionally supported programs in translational research and Precision Medicine. We anticipate that this WCM SPORE will become an important international partner for PCa research.

Aim 4: Train the next generation of PCa investigators. To reduce suffering and death from PCa, we must train the next generation of clinician/scientists and offer opportunities to established investigators in other fields to apply expertise towards PCa. The CEP and DRP will facilitate this goal. We will also leverage the WCM Clinical and Translational Science Center’s (CTSC) educational opportunities to facilitate career development.

In summary, the WCM SPORE in PCA will be a major hub for paradigm-shifting translational research. We will establish new approaches to treating PCA, which will result in improved patient survival and quality of life.

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Project 1: Non-invasive Clinical Assay for Early Detection of Treatment Resistance in Patients with Metastatic Prostate cancer

Co-Leader: Himisha Beltran, MD
Co-Leader: Francesca Demichelis, PhD
Co-Leader: Scott Tagawa, MD

Identifying patients with metastatic castration resistant prostate cancer (CRPC) that will no longer benefit from potent androgen receptor (AR)-directed therapies is an unmet need. We have developed a genomic signature associated with AR-independence and the neuroendocrine phenotype that can be detected non-invasively using plasma samples from patients. Based on strong expertise from our groups, our goal is to develop a targeted assay to assess tumor dynamics and clinical impact of AR-independent genomic alterations in predicting response to subsequent AR-targeted therapies. We will also define the spectrum and pattern of circulating tumor clones compared to matched biopsies in patients with metastatic CRPC using a whole exome sequencing approach. This study would lead to further clinical development of a non-invasive, plasma genomic biomarker with several areas of potential impact including early detection of patients transforming towards AR-independence leading to early cessation of AR therapy and consideration of metastatic biopsy to look for neuroendocrine transformation and platinum-based therapies.

Specifically, we will test the following hypotheses:

1) DNA alterations found in metastatic biopsies of CRPC can be detected in the circulation.

2) The emergence of circulating CRPC-NE-associated alterations in patients with CRPC is associated with shorter time on AR-directed therapies and other clinical features of AR independence.

Aim 1: Determine tumor dynamics and the clinical impact of circulating alterations in predicting response to AR-directed therapy.

Aim 2: Define the spectrum of circulating DNA alterations in patients with metastatic CRPC.

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Project 2: Targeting N-Myc and EZH2-driven Castrate Resistant Prostate Cancer

Co-Leader: Himisha Beltran, MD
Co-Leader: David Rickman, PhD

Transformation of castration resistant prostate cancer (CRPC) towards androgen signaling independence has emerged as a resistance mechanism in a subset of metastatic CRPC following exposure to androgen receptor (AR)-targeted therapies such as abiraterone or enzalutamide. Clinically, patients typically present with progression in the setting of a low or modestly rising serum prostate specific antigen (PSA) and metastatic biopsies can show pathologic or molecular features consistent with neuroendocrine prostate cancer (NEPC). NEPC is associated with low or absent AR expression, suppressed AR signaling, retention of early genomic mutations from its adenocarcinoma precursor, and acquisition of distinct genomic and epigenomic alterations. The development of novel therapeutic approaches for patients with NEPC represents a clinical unmet need. Over the last seven years, our group has focused on characterizing the molecular landscape of NEPC and have identified and validated new therapeutic targets, including the N-Myc/Aurora A pathway and specific epigenetic modifiers such as (Enhancer of Zeste Homolog 2) EZH2.

Our goal is to develop more effective targeting strategies for a biomarker-selected subgroup of late stage CRPC driven by N-Myc and less dependent on the AR. This will lead to a better understanding of the mechanisms underlying N-Myc/EZH2 driven NEPC and identified biomarkers of response to N-Myc and EZH2 inhibition. This study will serve as a solid preclinical foundation for the development of new biomarker-driven therapeutic strategies for treating patients with advanced prostate cancer.

Our overarching hypothesis is that N-Myc cooperates with both Aurora-A and EZH2 to drive the neuroendocrine phenotype and that characterizing this driving role will lead to more effective targeting strategies for this tumor entity.

Aim 1: Characterize the interaction between the EZH2 and N-Myc signaling in driving NEPC.

Aim 2: Develop novel allosteric compounds targeting N-Myc/Aurora-A complex.

Aim 3: Develop clinical biomarkers to predict response in targeting N-Myc and EZH2 in CRPC.

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Project 3: Toward Understanding Prostate Cancer Heterogeneity

Co-Leader: Mark A. Rubin, MD
Co-Leader: Scott Tomlins, MD, PhD
Co-Leader: Saravana Mohan Dhanasekaran, PhD

Although high risk localized prostate cancer is often cured by multimodal therapy including radical prostatectomy, radiation therapy [RT] and androgen deprivation therapy [ADT], the development of castration resistant prostate cancer (CRPC) after metastatic progression is lethal. Studies from several groups have profiled untreated localized prostate cancer and CRPC, however these studies represent static snapshots from convenient samples or rapid autopsies from earlier treatment eras. Lacking are molecular studies addressing prostate cancer progression during current treatments or clinical trials. Recently, a multi-institutional “Dream Team” was formed to perform whole exome (WES) and RNA sequencing on metastatic tumor biopsies (and germline DNA) from 500 CRPC patients (the “CRPC500” study) prior to enrollment on trials involving enzalutamide, abiraterone, and a PARP inhibitor (olaparib). We recently published the first 150 cases (Robinson et al., Cell 2015) and over 500 men have been enrolled with clinical follow-up expected through the next 3 years. We now have the extraordinary opportunity to examine the original untreated diagnostic material from the prostates of the CRPC500 patients and compare it to the metastatic samples to explore key critical questions relevant to progression to CRPC and treatment response.

This project will address 3 critical questions emerging from the CRPC500 trial. 1) What are early genomic/transcriptomic markers predicting metastatic CRPC development? 2) Are molecular alterations associated with intrinsic enzalutamide or abiraterone resistance present in the primary tumor? 3) Which set of mutations in DNA damage repair genes predict PARP inhibition response and when do they occur?

Our team developed next generation sequencing (NGS) assays enabling interrogation of formalin-fixed paraffin embedded (FFPE) samples. EXaCT-1 is a CLEP (CLIA) approved WES assay with an associated analysis pipeline used on over 700 metastatic sample/normal pairs (Weill Cornell Medicine). Complementing this assay is a PCa-specific version of the Oncomine Cancer Panel optimized for 10-20ng FFPE DNA and RNA (Univ. Michigan). These approaches allow analysis of untreated tumors from CRPC500 patients.

Our overarching goal is to determine the extent to which early mutations/other alterations inform on disease progression and response to AR or PARP directed therapy. We have formulated three specific aims.

Aim 1: Collect, characterize and immunohistochemically profile primary ADT-naïve specimens from CRPC500 trial patients.

Aim 2: Determine the molecular landscape of multiple tumor foci from the primary ADT-naïve CRPC500 specimens.

Aim 3. Identify molecular mediators of prostate cancer progression and track the progressing clone through an integrative molecular profiling analysis.

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Project 4: Targeting Genomic Instability in Distinct Subclasses of Prostate Cancer

Co-Leader: Christopher Barbieri, MD, PhD
Co-Leader: Michael M. Shen, MD
Co-Investigator: Robert Bristow, MD, PhD

Genomic instability is a fundamental feature of human cancer. Certain cancer types harbor underlying defects in DNA repair and thus are particularly susceptible to therapeutic strategies introducing DNA damage (e.g., BRCA1 mutant breast and ovarian cancers). In prostate cancer, structural genomic rearrangements, including translocations and copy number aberrations, are a common mechanism driving tumorigenesis. However, genetic alterations in prostate cancer predisposing to chromosomal rearrangements remain largely undefined. Whole genome sequencing demonstrates that prostate cancer harboring recurrent point mutations in SPOP (SPOPmut) display significantly higher numbers of genomic rearrangements compared with other clinically localized prostate cancer. These observations raise the possibility that SPOP mutations, early events in prostate cancer tumorigenesis, lead to genomic instability.

Preliminary studies demonstrate that around 10% of prostate cancer are SPOPmut, and these represent a distinct molecular subclass. Preliminary studies in vitro demonstrate that cells expressing SPOP mutations accumulate DNA double-strand breaks (DSBs) due to altered DNA repair processes. Relevant to this SPORE project, we have shown that SPOP mutation results in increased sensitivity to DNA-damaging therapeutic agents such as ionizing radiation and poly (ADP-ribose) polymerase (PARP) inhibitors. Based on these observations, we hypothesize that SPOP mutation promotes accumulation of genomic rearrangements through impaired DSB repair and the SPOPmut subclass of prostate cancer may be selectively responsive to DNA-damaging therapeutics, nominating alternative treatment strategies.

This highly collaborative project brings together established investigators supported by the PCF and SU2C-PCF who will now study the translational aspects of SPOPmut prostate cancer. Using organoids, state-of-the-art mouse models, and cutting edge patient analyses, we will impact how clinical trials using DNA-damaging agents are rationally designed and analyzed.

Aim 1. Define the impact of SPOP mutation on genomic instability and therapeutic vulnerability using novel in vitro platforms.

Aim 2. Establish the role of SPOP mutation in DNA damage and repair using a novel genetically engineered mouse model.

Aim 3. Determine the association of SPOP mutation with response to radiotherapy for clinically localized PCa.

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Administrative Core

Co-Director: Massimo Loda, MD
Co-Director: Lewis Cantley, PhD

The Administrative Core will provide the Weill Cornell Medicine (WCM) SPORE in Prostate Cancer with robust leadership and efficient organization including the necessary administrative services to ensure the overall program operates successfully. The Administrative Core will function to serve the Program in areas of grant management, general administration, meeting planning, administrative data management, regulatory issues, interactions with the NCI, and communications. Essential to the success of the SPORE Program is the leveraging and coordination of existing institutional resources and the scheduling of advisory board meetings to support and review the SPORE’s scientific advancement. Therefore, the overall goal of the WCM SPORE’s Administrative Core is to manage the non-technical needs of the SPORE Program including facilitating scientific oversight and ensuring the scientific goals of the program are met. We believe the administrative team should provide an outstanding supportive environment to allow our investigators to focus on the scientific and translational aspects of the research.

The SPORE Administrative Core will assure the program is well integrated into the local research community. Integration with the Edward and Sandra Meyer Cancer Center (MCC), the Clinical and Translational Science Center (CTSC), the Weill Cornell Medical School, and New York-Presbyterian Hospital (NYPH) will ensure that the WCM Prostate Cancer SPORE can maximally leverage existing programs and resources.

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Biospecimen Core

Co-Director: Brian Robinson, MD
Co-Director: Juan Miguel Mosquera, MD
Co-Director: Massimo Loda, MD

The Biospecimen Core will provide collaborating investigators with both high-quality tissue samples (e.g., blood, urine, and surgical samples) and interpretative and consultative pathology services. Our over-arching goal is to facilitate translational research through collection of highly annotated biological material and associated clinical information. Thus, one of the major goals of this Core is to maintain and grow an existing tissue, urine, and blood resource (henceforth referred to as the “Biobank”), which is linked to clinical outcome data within a secure data management system that will be available to Weill Cornell Medicine (WCM) SPORE in Prostate Cancer investigators as well as SPORE investigators at other institutions.

Specific Aims. There are some guiding principles, which are critical to the success of this Core and allow us a means of presenting the various facets of our Biospecimen Core.

  1. Successful translational research requires a wide range of well-annotated human analytes, tumor organoids, mouse models, and xenografts.
  2. Data generated from each sample increases its value.
  3. High quality pathology interpretation and expertise in methodology is critical to working with heterogeneous PCa samples to ensure their optimal use.
  4. Synergy with pre-existing programs leads to economy of effort.
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Computation Biology and Biostatistics Core

Co-Director: Olivier Elemento, PhD
Co-Director: Karla Ballman, PhD
Co-Investigator: Andrea Sboner, PhD
Co-Investigator: Francesca Demichelis, PhD

The Computational Biology and Biostatistics Core (CBBC) will provide essential computational and biostatistical services and resources for all projects of the WCM SPORE in Prostate Cancer (PCa). Analytic services include statistical design and analysis, extensive quality control, integrative analysis and interpretation of genomic (DNA-seq, RNA-seq) epigenomic (ChIP-seq, bisulfite sequencing) datasets and implementation and development of custom computational pipelines needed by the projects. In addition to analytic services, the Computational Biology and Biostatistics Core will provide centralized access to several computational tools developed by the core investigators as well as direct access to expertise for the design and analysis of genomic and epigenomic experiments. The Computational Biology and Biostatistics Core will take advantage of the shared computational infrastructure of the Institute for Computational Biomedicine (ICB) at Weill Cornell Medicine (WCM) and of clinical-grade computational pipelines already developed in the context of the WCM/NewYork-Presbyterian Hospital (NYPH) Englander Institute for Precision Medicine (IPM). The Core will also be key to enabling data sharing and synergy between projects. The Core members are involved in other important genomic initiatives, including The Cancer Genome Atlas (TCGA)/International Cancer Genome Consortium (ICGC), NCI’s Early Detection Research Network (EDRN), the Encyclopedia of DNA Elements (ENCODE). Dr Elemento together with SPORE PI Dr Rubin and investigators at the New York Genome Center were recently awarded an NCI U24 grant to become a Specialized Genomic Data Center that will be a part of the Genomic Data Analysis Network (TCGA next phase).

Aim 1: To provide computational analysis of genomic, epigenomic, and transcriptional profiling for all Projects and Cores that are part of this SPORE

Aim 2: To provide the full spectrum of statistical services for all Projects and Cores that are part of the SPORE

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Developmental Research Program

Co-Director: David Nanus, MD
Co-Director: Paraskevi Giannakakou, PhD

The objectives of the Developmental Research Program (DRP) are to identify and provide funding for innovative research projects in PCa, each with the potential to evolve into translational/clinical studies with meaningful human endpoints; to provide funding to high-quality projects that complement and enhance the overall goals of the SPORE; to ensure there is a sustained stream of innovative translational research projects within the SPORE; and to develop a mechanism to identify and promote outstanding work from investigators at our Tri-institutional Campus, who may or may not have prior expertise in PCa research.

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Career Enhancement Program

Co-Director: Lorraine Gudas, PhD
Co-Director: Douglas Scherr, MD

The Career Enhancement Program aims to educate and mentor physician investigators and scientists in the conduct of PCa translational research.

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