Vanderbilt-Ingram Cancer Center SPORE in Gastrointestinal Cancer
Vanderbilt University Medical Center
Principal Investigator(s):
Robert Coffey, MD
- Principal Investigator(s) Contact Information
- Overview
- Project 1: Interrogating Distinct Tumor-Initiating Cells in CRC
- Project 2: Targeting Glutamine Metabolism to Enhance Egfr Blockade in Wild-Type Ras CRC
- Project 3: Targeting MYC in CRC
- Administrative Core
- Tissue Pathology and Cellular Analysis Core
- Preclinical Models Core
- Biostatistics and Bioinformatics Core
- Developmental Research Program
- Career Enhancement Program
Principal Investigator(s) Contact Information
Robert Coffey, MD
Professor of Medicine and Cell and Developmental Biology
Vanderbilt University Medical Center
2213 Garland Avenue, 10415 MRB IV
Nashville, TN 37232
(615) 343-6228
Overview
The Vanderbilt-Ingram Cancer Center (VICC) SPORE in GI Cancer continues to focus on colorectal cancer (CRC), the second leading cause of cancer deaths in the United States. Our previously funded GI SPORE enjoyed 16 years of continuous funding.
Vanderbilt’s GI SPORE has made discoveries and advances that hold great promise toward improved management of individuals with CRC. These include 1) successful development of a multi-pronged program to inhibit K-RAS and its licensing to the pharmaceutical industry, 2) identification of a mechanism-based strategy to target MYC, 3) proteogenomic characterization of CRC, 4) development, biological validation and clinical implementation of novel molecular imaging modalities to predict early response to treatment, 5) creation of novel stem-cell based mouse models of colonic cancer and 6) development and deployment of unique, complementary, high-throughput technologies to analyze proteins and signaling pathways at single cell resolution.
Our potential for continued success is high based on 1) productivity during the past funding cycles, 2) exceedingly strong institutional support, 3) recruitment of talented investigators to the field of GI cancer through career enhancement and developmental research funding, 4) access to unparalleled resources for drug discovery and small animal imaging, 5) a blend of young and seasoned clinical investigators and basic scientists working together in a highly collegial environment, 6) a committed group of patient advocates now organized into a Patient Advocacy Council and 7) multiple inter-SPORE, pharmaceutical, national and international horizontal and vertical collaborations.
Project 1: Interrogating Distinct Tumor-Initiating Cells in CRC
Project Co-Leaders:
Robert J Coffey, MD (Clinical Co-Leader)
Ken Lau, PhD (Basic Co-Leader)
A major therapeutic barrier in advanced colorectal cancer (CRC) is tumor recurrence after treatment. The “cancer stem cell hypothesis” posits that rare populations of cancer cells with stem cell characteristics, also known as tumor-initiating cells (TICs), fuel tumor growth, resist therapy, and repopulate the tumor at distal sites. In the normal colon, multiple stem cell populations exist in a reserve-to-active continuum. We hypothesize that distinct TIC populations exist in CRC, and these distinct populations of TICs have different clonogenic properties and tumor-repopulating potential. Using TICs marked by Lrig1 and Lgr5 to represent reserve and active TICs, respectively, we will use novel single-cell approaches to investigate the behaviors of these populations in the context of therapeutic intervention. First, we will determine whether there is a defined directional hierarchy where reserve TICs give rise to active TICs versus mutual interconversion. Second, we will determine whether TICs with malignant characteristics pre-exist in the primary tumor or if TICs acquire these characteristics de novo as a result of treatment. Third, we will determine whether a signature derived from TIC behaviors provides prognostic and/or predictive information for individuals with CRC. Our translational goal is to apply a systems approach to predict likelihood of tumor recurrence based on properties of TIC populations with the long-term goal of using combinatorial pathway alterations to target TIC behaviors.
Project 2: Targeting Glutamine Metabolism to Enhance Egfr Blockade in Wild-Type Ras CRC
Project Co-Leaders:
Jordan Berlin, MD (Clinical Co-Leader)
H. Charles Manning, PhD (Basic Co-Leader)
A wealth of proteogenomic information has provided a deep understanding of the molecular pathogenesis of CRC and has led to improved classification systems of the disease. However, matching a CRC patient to the optimum therapeutic regimen remains a major challenge. Epidermal growth factor receptor (EGFR) neutralizing monoclonal antibodies (mAbs; e.g., panitumumab) are approved for patients with advanced wild-type (WT) RAS CRC. However, in late-line therapy, only 12-17% of patients exhibit durable responses to EGFR mAb monotherapy and addition of EGFR mAbs to standard chemotherapy has limited clinical benefit. Clearly, therapeutic strategies that enhance efficacy of EGFR mAb and/or overcome resistance are needed, along with novel ways to prioritize patients for such therapy. The metabolic requirements of proliferating cells link signal transduction with nutrient accumulation, resulting in a direct link between proliferation and metabolism. Glutamine (Gln) is a key anaplerotic substrate used by cancer cells, providing energy, carbon, and nitrogen to meet the demands of rapid and sustained growth. Gln replenishes the supply of tricarboxylic acid (TCA) cycle intermediates used to fuel biosynthesis, and also plays a critical role in depleting cytotoxic reactive oxygen species (ROS). In many cancers, EGFR and Gln cooperate to provide both ‘signals’ and ‘fuel’, which are required for mitogen activated protein kinase (MAPK)-dependent growth and proliferation. The Scientific Premise of this project is that Gln provides a ‘fuel’ source to support EGFR-mediated proliferation; blocking Gln metabolism will deplete a critical metabolic ‘fuel’ required for cell growth and proliferation. The Overall Hypothesis is that inhibition of Gln metabolism will enhance EGFR mAb therapy for a select group of patients with CRC who have failed prior EGFR mAb-containing regimens. We will evaluate non-invasive PET imaging as a biomarker of Gln avidity, from which we will develop a Gln PET-derived gene signature. A gene signature of Gln avidity will allow this information to be utilized in lieu of complex positron emission tomography (PET) imaging.
Project 3: Targeting MYC in CRC
Project Co-Leaders:
Stephen Fesik, PhD (Basic Co-Leader)
William Tansey, PhD (Basic Co-Leader)
R. Daniel Beauchamp, MD (Clinical Co-Leader)
Recurring genetic perturbations in colorectal cancer (CRC) activate MYC, an oncogenic transcription factor that features prominently in human cancer. Despite the pervasive involvement of MYC in CRC, and a wealth of studies demonstrating that genetic inhibition of MYC promotes frank tumor regression in mouse model systems, MYC is generally considered undruggable. Indeed, there are currently no drug-like molecules capable of directly blocking MYC function in cancer cells. Recently, however, we presented a new paradigm for target gene recognition by MYC that also created a new opportunity to discover drugs that block MYC function. We found that the stable association of MYC with chromatin depends on its direct interaction with the chromatin scaffolding protein WDR5, which co-localizes broadly with MYC across the genome and facilitates MYC binding to target genes. Structural analysis revealed that MYC binds WDR5 by engaging a shallow, hydrophobic cleft on the surface of WDR5 that is well-suited for drug discovery. The goal of this project is to target the MYC-WDR5 interface to discover a drug that will disable MYC function in CRC by preventing the stable association of MYC with target gene chromatin. This project combines drug discovery, structural biology, medicinal chemistry, biochemistry, and cutting-edge genomic approaches, along with powerful model systems, to identify, refine, and validate drug-like molecules that disrupt the MYC-WDR5 interaction, and to explore their effectiveness as anti-cancer agents against CRC. Within the five-year funding period, we intend to produce first-in-class MYC-WDR5 inhibitors that will be fully validated for their utility in treating CRC and ready to proceed to Investigational New Drug (IND)-enabling studies. Successful completion of this project will address a clear unmet clinical need for targeted anti-MYC therapies, which are expected to have broad efficacy against CRCs for which there are only limited treatment options. Drugs discovered in this program will likely also have utility against a wide spectrum of cancer types.
Administrative Core
Core Directors:
Robert J. Coffey, MD (Co-Director)
Jordan Berlin, MD (Co-Director)
The Vanderbilt-Ingram Cancer Center SPORE in Gastrointestinal (GI) Cancer Administrative Core will support all GI SPORE cancer-related research projects and investigators by managing SPORE resources, communication, and outreach, and by fostering interactions among investigators, collaborators, other Vanderbilt-Ingram Cancer Center SPOREs, other GI SPOREs, the patient and advocate community, and the National Cancer Institute. This management and support will be accomplished by administrative and scientific meetings of GI SPORE investigators with oversight provided by the Internal and External Advisory Boards.
Tissue Pathology and Cellular Analysis Core
Core Directors:
M. Kay Washington, MD, PhD (Co-Director)
Ken Lau, PhD (Co-Director)
The Translational Pathology and Cellular Analysis Core (TPCA) builds upon over 20 years of productive collaborations by Dr. Washington with other GI SPORE investigators to support GI SPORE projects and pilot projects by providing high-quality biospecimens and research histology.
Preclinical Models Core
Core Directors:
Todd Peterson, PhD (Co-Director)
Bhuminder Singh, PhD (Co-Director)
The Preclinical Models Core (PCMC) will play a central role in the translational research mission of the Vanderbilt-Ingram Cancer Center (VICC) SPORE in Gastrointestinal (GI) Cancer, providing state-of-the-art imaging resources for three projects, future pilot and feasibility studies, and developmental research. The PCMC will leverage existing, institutionally-supported equipment and infrastructure to offer a full range of small animal and human functional, molecular, and anatomical imaging resources, including magnetic resonance imaging (MRI), computed tomography (CT), digital X-ray, optical, single photon emission computed tomography (SPECT), and positron emission tomography (PET). A unique feature of this core, VICC GI SPORE investigators will also have access to novel probe development resources that leverage the capabilities of the Vanderbilt Center for Molecular Probes (CMP), including high-throughput, diversity-oriented synthesis capabilities suitable for developing novel imaging compounds, as well as world-class preclinical and cGMP resources of the CMP radiochemistry facility. The core will establish and curate colorectal cancer patient-derived xenografts (PDXs) and patient-derived tumor organoids (PDOs) of defined genetic background and drug sensitivity/resistance to conduct the translational studies to overcome or delay emergence of drug resistance.
Biostatistics and Bioinformatics Core
Core Director:
Yu Shyr, PhD
The purpose of the Biostatistics and Bioinformatics Core (BBC) is to provide professional expertise in biostatistics and bioinformatics for all Vanderbilt-Ingram Cancer Center (VICC) SPORE in Gastrointestinal (GI) cancer projects, investigators, and participants. Functions provided by this core include development of experimental designs and power and sample size analysis; data quality control; statistical and bioinformatic analysis and interpretation of findings; and collaboration on presentation of results.
Developmental Research Program
Program Director:
Cathy Eng, MD
The Developmental Research Program (DRP) is designed to broaden the translational research efforts of the Vanderbilt-Ingram Cancer Center SPORE in Gastrointestinal (GI) Cancer by funding "pilot projects" or early stage, short term (≤ 2 years) projects with limited preliminary data but have the potential to lead to significant advances. To promote translational research in GI cancer, the DRP will fund innovative and high-quality research in GI malignancies that have the potential to enhance existing SPORE projects, support future SPORE projects, be elevated to a full GI SPORE project, and/or to lead to independent grant support.
Career Enhancement Program
Program Director:
Richard M. Peek, Jr., MD
The goal of the Vanderbilt-Ingram Cancer Center SPORE in Gastrointestinal (GI) Cancer (VICC GI SPORE) Career Enhancement Program (CEP) is to provide individuals with the training, mentorship, and collaborative interactions necessary for them to have successful and independent careers in translational GI cancer research.