Rubin Lab

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Research

BIOMARKERS OF PROSTATE CANCER PROGRESSION AND HETEROGENEITY

While localized prostate cancer is highly curable, metastatic castration-resistant prostate cancer (CRPC) progressing after androgen deprivation therapy (ADT) remains treatment resistant.  The molecular mediators of progression to CRPC are poorly understood, particularly in an individual patient.  Likewise, prostate cancer is often multifocal at diagnosis, and pathologists must identify the biologically relevant (“index”) focus.  Our team has extensive experience in prostate cancer pathology, next generation sequencing, genomics and computational biology/statistics.  These areas of expertise guide our research projects.

A Precision Medicine Approach to Prostate Cancer Active Surveillance

Active surveillance is often used for low grade, early stage prostate cancer and includes closely monitoring tumor progression and withholding other treatments such as radiation or surgery.  By investigating novel tissue-based biomarkers to determine the presence of, or progression to, aggressive disease in early stage prostate cancer our aim is to prove that these biomarkers will reliably predict progression and/or under-staging and grading.

Functional Validation of Prostate Cancer Driving Mutations

Prostate cancer tumors exhibit a variety of mutations. To examine the functional relevance of genes implicated by these somatic mutations, we are currently developing companion functional approaches for the analysis of DNA and RNA sequencing and determining key targetable genes associated with prostate cancer.      

Integrative Genomics of Prostate Cancer Progression

By identifying the molecular mediators of progression to CRPC, our team will inform on the actual impact of multifocality/heterogeneity and determine the optimum approach to identify the true ‘index’ focus at prostatectomy.

Towards Understanding Prostate Cancer Heterogeneity

Our aim is to define the role of SPOP mutations in prostate cancer and elucidate the biology of SPOP mutant prostate cancer as a distinct molecular subclass

 

IN VITRO MODELING & FUNCTIONAL VALIDATION OF IDENTIFIED MUTATIONS

Targeting Genomic Instability in SPOP Mutant Prostate Cancer

The major goals of this project are to define mechanisms of DNA repair alterations and translational implications in SPOP mutant prostate cancers using organoids mouse models, and in vivo analyses of patient samples.

 

PATIENT-DERIVED ORGANOID MODELS

In vitro and in vivo Pre-clinical Model Development

Our active program is focused on the development of 3D organoids derived form metastatic biopsies that, in combination with individualized genomic sequencing, nominates drug candidates and drug resistance in a precision patient setting.  The overarching goal is to predict resistance and/or direct the next line of therapy as well as to create a biorepository of prostate cancer and other tissue type organoids for future research.

 

NEUROENDOCRINE PROSTATE CANCER

Neuroendocrine Prostate Cancer (NEPC) is a highly lethal subtype, most often occurring due to cellular resistance to otherwise successful treatment therapies of adenocarcinoma. By defining somatic copy number alterations associated with the emergence of NEPC and determining the spectrum of mutations we hope to further investigate the functional activity of NEPC genes.

Targeting and mechanistic insights underlying N-Myc driven Neuroendocrine Prostate Cancer

The aim of this study is to characterize the driving role of N-Myc and AURKA in neuroendocrine prostate cancer with the ultimate goal of more effectively targeting this tumor subclass by disrupting this complex.

Identification of Neuroendocrine Prostate Cancer (NEPC)-Specific Antigens and Antibodies (Janssen Pharmaceuticals)

In this study we will identify neuroendocrine prostate cancer (NEPC) cell surface antigens for the development of novel antibody therapeutics for the treatment of this aggressive subgroup of prostate cancer

Development of Novel Therapeutics for treatment of Neuroendocrine Prostate Cancer  (Eli Lilly)

Our lab is focused on evaluating the activity of the Lilly Aurora kinase inhibitor both in vitro and in vivo.  Critical to this project is the use of novel preclinical models of NEPC; specifically PDX animal model and biologic/molecular readouts of Aurora-N-myc activity with a focus on organoid studies.                 

Characterizing Molecular Determinants of Response to LY2835219 in Advanced Prostate Cancer  (Eli Lilly)

We are currently evaluating the frequency and clinical impact of CDK4 and CDK6 amplifications, CCND1 amplification, and RB1 loss in hormone naïve, castration resistant, and neuroendocrine prostate cancer. We are also using novel patient-derived organoid models to understand the biologic role of these alterations and the functional impact of response to LY2835219, as well as other potential biomarkers of response.

Characterizing AR negative NEPC as a mechanism of resistance to enzalutamide

One emerging mechanism in prostate cancer patients involves loss of AR signaling dependence and transition to a neuroendocrine (NE) phenotype. Early detection remains challenging.  Our goal is develop an AR negative neuroendocrine cell line that shows resistance to enzalutamide treatment.

DNA DAMAGE AND REPAIR

Interrogation of aberrant DNA repair in sporadic prostate cancer

The goals of this study are to identify and determine the frequency of aberrations in DNA damage response pathways enriched in castration resistant prostate cancer, to determine the clinical relevance of these DNA repair defects, evaluate the functional and biological consequences of these DNA repair defects, and identify new therapeutic strategies for patients with advanced prostate cancer.

 

LONG NON-CODING RNAs IN PROSTATE CANCER PROGRESSION

In this study we investigate the role of the estrogen receptor (ER-alpha) regulated long non-coding RNA, NEAT1, in PCA. Preliminary studies have shown that ER-alpha is recruited to both coding and noncoding regions of the prostate genome and orchestrates expression of non-coding regulatory RNAs, thus identifying the long non-coding RNA NEAT1 as a downstream mediator of ER-alpha signaling. In addition, analysis of a large clinical cohort suggested that NEAT1 is a novel prognostic biomarker of clinically aggressive disease and a predictive biomarker of patients with advanced PCA.

 

Weill Cornell Medicine Rubin Lab Belfer Research Building
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