The Memorial Sloan Kettering Cancer Center
Principal Investigator
Robert Coffey, MD
Robert Coffey, M.D.
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) Specialized Program of Research Excellence (SPORE) in GI Cancer continues to focus on colorectal cancer (CRC), the second leading cause of cancer deaths in the United States. Building upon our past success and leveraging institutional resources and support, we propose three projects that aim to develop and deploy small molecules against two supposedly undruggable targets that drive colorectal cancer, MYC and β-catenin, as well as overcoming immune exclusion in individuals with microsatellite stable colorectal cancer that makes up 85% of colorectal cancer and these individuals do not respond to immunotherapy. We aim for practice-changing approaches to the diagnosis and treatment of colorectal cancer
Project 1: Overcoming Immune Exclusion in Microsatellite Stable Colorectal Cancer
Project Co-Leaders
- Jordan Berlin, M.D. (Clinical Co-Leader)
- Robert J Coffey, M.D. (Basic Co-Leader)
- Ken Lau, Ph.D. (Basic Co-Leader)
Specific Aims
Although immune checkpoint inhibitors (ICIs) are highly effective in microsatellite unstable (MSI-H) colorectal cancer (CRC), it has a limited clinical benefit for the 85% of CRCs that are classified as microsatellite stable (MSS). This is due, at least in part, to a paucity of CD8+ T cells present in these tumors. The aim of Project 1 is to overcome this lack of intratumoral CD8+ T cells, which we use as our definition of immune exclusion (IEX), in MSS CRC. We recently discovered a four-gene signature associated with IEX and worse progression-free survival in MSS CRC. We also discovered that two of the protein products of that signature, DDR1 and TGFBi, are present in supermeres, a secreted amembranous nanoparticle we recently identified. Levels of DDR1 and TGFBi are markedly increased in plasma-derived supermeres of CRC patients. In triple-negative breast cancer, the shed ectodomain of DDR1, a collagen-activated receptor tyrosine kinase, binds to the extracellular matrix so that CD8+ T cells are excluded from the tumor, with these T cells gaining entry into the tumor following administration of a neutralizing antibody to DDR1. Project 1 is participating in a clinical trial that introduces the neutralizing antibody to DDR1 (PRTH-101) along with the ICI pembrolizumab (Pembro) to cancer patients. The premise is that PRTH-101 will allow CD8+ T cells to enter the tumor proper, and Pembro will overcome an immune checkpoint to unleash the anti-tumor cytotoxic activity of these CD8+ T cells. Additional goals of this project are to refine the IEX signature to determine markers of non-responsiveness to ICI therapy in MSI-H, as well as to explore the diagnostic and therapeutic implication of DDR1 and TGFBi in supermeres.
Project 2: Targeting MYC in Colorectal Cancer
Project Co-Leaders
- Kristen Ciombor, M.D. (Clinical Co-Leader)
- William Tansey, Ph.D. (Basic Co-Leader)
Specific Aims:
The goal of Project 2 is to develop a new targeted therapy to treat colorectal cancer (CRC) by selectively inhibiting the ability of the MYC oncoprotein transcription factor to enhance ribosomal protein gene (RPG) expression. MYC is frequently dysregulated in CRC and is considered a highly validated target for treatment of a broad range of malignancies. MYC itself, however, is undruggable, meaning that innovative new strategies are needed to pharmacologically block MYC function in CRC. This project targets MYC via its chromatin cofactor WDR5, which recruits MYC to regulatory elements of ribosomal protein genes, enhancing their expression. We recently declared a clinical candidate inhibitor of the “WIN site” of WDR5, which displaces WDR5 from chromatin and evicts MYC from RPG promoters. This candidate is now moving forward to IND enabling in conjunction with the NCI Experimental Therapeutics (NExT) Program. In this project, we will gather essential new information to support the clinical implementation of a WDR5 inhibitor for the treatment of CRC, determining patient selection criteria, identifying surrogate biomarkers, and culminating in a phase II clinical trial to determine the efficacy of WDR5 inhibition in CRC patients. Completion of this project will result in the first-in-class trial of a new therapy for patients with metastatic CRC for which there are currently limited treatment options.
Project 3: Characterization of β-Catenin Degraders for the Treatment of Colorectal Cancer
Project Co-Leaders
- Cathy Eng, M.D. (Clinical Co-Leader)
- Stephen Fesik, Ph.D. (Basic Co-Leader)
- Ethan Lee, M.D., Ph.D. (Basic Co-Leader)
- Vivian Weiss, M.D., Ph.D. (Basic Co-Leader)
Specific Aims
The long-term objective of this study is to investigate how a new class of compounds, β-catenin degraders, can be exploited to target Wnt/ β-catenin (henceforth Wnt)-driven colorectal cancers (CRCs). Aberrant activation of the Wnt pathway drives the initiation and progression of nearly all CRCs. To date, no drugs inhibiting the Wnt pathway have been FDA-approved due to a lack of druggable targets that can bypass common Wnt pathway mutations in CRC. In a conceptual breakthrough, using an NMR-based fragment screen followed by X-ray guided medicinal chemistry with support from NCI’s Chemical Biology Consortium, we have discovered small molecules that bind with nanomolar affinity to β-catenin, the central regulator of the Wnt pathway. These compounds were used to create chimeric small molecule-based PROTACs that degrade β-catenin in CRC cells with pathway-activating mutations. We have shown that β-catenin degradation occurs via the ubiquitin-proteasome pathway and that the PROTAC degraders can inhibit the expression of Wnt target genes. Furthermore, this class of compounds inhibits the growth of both CRC cells and spheroids from a β-catenin mutant CRC cell line. These highly potent PROTACs also degraded β-catenin and inhibited Wnt pathway signaling in vivo, using CRC cell line xenografts in nude mice. We thus demonstrate that β-catenin PROTACs may provide a new means for controlling aberrant Wnt signaling and lay a foundation for the discovery of a novel treatment for nearly all CRCs. This project aims to use cutting-edge sophisticated in vitro, ex vivo, and in vivo approaches to better understand the effects of β-catenin degradation in CRC, thereby enabling their clinical translation. We propose to characterize the mechanism of action of the β-catenin PROTACs in CRC, determine the therapeutic window and potential toxicities associated with β-catenin degradation, and provide proof of principle for the effectiveness of β-catenin PROTACs in CRC patient-derived organoids (PDOs), CRC cell line xenografts, and a stem cell-driven mouse model of colorectal neoplasia. We propose three specific aims: 1) test the sensitivity of CRC cell monolayers and spheroids to β-catenin PROTACs; 2) determine the extent of PROTAC-induced degradation of E-cadherin-associated β-catenin; and 3) examine the effects of PROTACs in CRC cell line xenografts and Lrig1CreERT2;Apcflox/+ mice. At the end of this funding period, we will have fully characterized high-quality β-catenin PROTAC drug candidates, enabling their progression to IND-enabling studies.
Administrative Core
Core Directors
- Robert J. Coffey, M.D. (Co-Director)
- Jordan Berlin, M.D. (Co-Director)
Specific Aims
The Administrative Core will support the Vanderbilt-Ingram Cancer Center (VICC) SPORE in Gastrointestinal (GI) Cancer projects and investigators by 1) managing SPORE resources, communication and outreach, 2) fostering the interaction among investigators, collaborators, other SPOREs (including the VICC SPORE in Breast Cancer), the patient and advocate community, and 3) maintaining close ongoing interactions with the National Cancer Institute Translational Research Program. This management and support will be accomplished through a series of oversight committees and organized administrative and scientific meetings of GI SPORE investigators, institutional representatives, and external advisors.
Biospecimens Core: Tissue Pathology and Cellular Analysis
Core Directors
- M. Kay Washington, M.D., Ph.D. (Co-Director)
- Ken Lau, Ph.D. (Co-Director)
Specific Aims
The Translational Pathology and Cellular Analysis (TPCA) Core plays a central role in the translational research mission of this SPORE by providing essential support for all projects by providing annotated human biospecimens and research histology services. It includes spatial and single-cell profiling services under the direction of Dr. Ken Lau. This sub-core enables technologies for quantifying and analyzing protein expression at a multiplex, single-cell level, greatly augmenting the histopathology capabilities of the TPCA. While the primary mission of the TPCA is state-of-the-art immunohistochemistry, research pathology and biorepository services, the cellular analysis sub-core offers three cutting-edge technologies: single-cell RNA-Seq, MxIF, and spatial transcriptomics, with an emphasis on application to human FFPE specimens. The sub-core offers services, from the preparation and processing of samples, the generation and verification of probe reagents, and screening and validation of targets using in situ hybridization. Customization of non-routine profiling assays are also developed in collaboration with the various SPORE projects. Data generated is synthesized and presented to investigators and the BBC for seamless downstream integrative analyses. The TPCA also has synergistic, bidirectional interactions with the PCMC by providing tissues to generate in vitro models, as well as by characterizing these models with profiling technologies. The TPCA partners with other established tissue collection and immunohistochemistry shared resources, such as the Vanderbilt University Medical Center Translational Pathology Shared Resource and the Digital Histology Shared Resource, to provide exceptional services to the GI SPORE in a highly cost-effective manner. Close collaboration with the Biostatistics and Bioinformatics Core provides the TPCA and GI SPORE with robust informatics and database tools for collection, distribution, and annotation of biospecimens in the GI SPORE repository.
Biostatistics and Bioinformatics Core
Core Director
Specific Aims
The Biostatistics and Bioinformatics Core (BBC) provides essential biostatistics and bioinformatics expertise for all projects within the Vanderbilt-Ingram Cancer Center (VICC) SPORE in Gastrointestinal (GI) Cancer. Leveraging extensive statistical knowledge and advanced computational resources, the BBC ensures rigorous experimental design, robust data management, and sophisticated analysis methodologies to support innovative translational research.
BBC members engage collaboratively with GI SPORE investigators from project inception through completion, ensuring the statistical validity and bioinformatics integrity of each study. During the study planning phase, BBC personnel assist investigators in clearly defining research objectives, selecting appropriate study designs, analyzing preliminary data, establishing blinding and randomization schemes, determining interim monitoring strategies and early stopping rules, calculating adequate sample sizes that balance statistical and clinical significance, and precisely formulating analysis plans. Core members also draft comprehensive statistical sections for research protocols and grant applications.
Furthermore, BBC personnel collaborate closely with investigators and the Tissue Pathology and Cellular Analysis Core (TPCAC) to develop tailored data management solutions. These solutions include creating or refining data capture systems, integrating existing or newly developed platforms, implementing automation to enhance efficiency, and establishing rigorous data quality control pipelines.
Throughout study execution, the BBC proactively monitors data accrual, maintains data quality through continuous quality checks, addresses emerging data concerns promptly, performs interim analyses, and monitors study safety. Additionally, core members prepare, adapt, or refine analytical methods aligned with evolving research requirements and rigorously test analysis pipelines to ensure validity and reproducibility.
Upon study completion, the BBC oversees comprehensive final analyses, generating accurate statistical summaries, figures, and bioinformatics results. The core also contributes significantly to the preparation of manuscripts, ensuring clear, accurate, and impactful reporting of findings.
Overall, the BBC enhances the scientific rigor and translational impact of VICC GI SPORE projects through dedicated biostatistical and bioinformatic collaboration.
Preclinical Models Core
Core Directors
- Nicholas Zachos, Ph.D. (Co-Director)
- Bhuminder Singh, Ph.D. (Co-Director)
Specific Aims
The Preclinical Models Core (PCMC) serves as a central repository for generation, propagation, and characterization of patient-derived organoids (PDOs) from both normal and colorectal cancer (CRC) tissue, as well as isolation of innate immune and participant-matched cytotoxic CD8+ T cells. The PCMC provides technical expertise to conduct key experiments using these resources. The PCMC provides support to all three projects within the GI SPORE and interacts closely with the Tissue Pathology and Cellular Analysis Core (TPCA) and the Biostatistics and Bioinformatics Core (BBC).
The PCMC is established to support this GI SPORE in developing and testing novel therapeutic strategies to treat CRC using physiologically relevant complex PDO models. The PCMC utilizes its extensive expertise in PDO methodologies to establish and characterize complex models that recapitulate various aspects of CRC tumors and their microenvironment that include stromal and immune cells. The overarching goal is to validate molecular targets of therapeutic strategies developed by the Projects in a preclinical setting using PDOs that include relevant fibroblast and immune cell types. The PCMC coordinates efforts, consolidate resources, and shares experimental expertise by pursuing three Specific Tasks: 1) Generate, maintain, and characterize the CRC PDO biobank; 2) Provide expertise and resources to generate or establish epithelial-only PDO cultures as well as additional complex models, including air-liquid-interface (ALI) cultures and PDOs derived by fine-needle-aspiration (FNA), which self-organize in vitro with multiple stromal/immune cell types; and 3) Provide technical expertise for differentiating colonic PDO models.
The immediate goal of the PCMC is to provide support to all three of our projects and the TPCA and BBC. Core personnel work closely with projects and other core leaders to ensure effective support and two-way communication. The longer-term goal of the PCMC is the wider dissemination of these resources and expertise to provide relevant preclinical models that serve as a precision-medicine platform for treatment of CRC patients.
Developmental Research Program
Program Director
Specific Aims
The overall objective of the Developmental Research Program (DRP) within the Vanderbilt-Ingram Cancer Center (VICC) SPORE in Gastrointestinal (GI) Cancer (hereafter, VICC GI SPORE) is to encourage innovative translational research in GI cancer. The DRP is led by a Director (Richard Peek, MD) and is supported by the Developmental Research Advisory Committee (DRAC) comprised of senior investigators at Vanderbilt, Meharry Medical College (MMC), and Tennessee State University (TSU). This alliance allows for the identification of talented DRP candidates with varied scopes of expertise and ensuring innovative science. The DRP leadership has significant crossover with the leadership of the Career Enhancement Program (CEP) to encourage CEP recipients to apply for DRP funding and to identify promising investigators from DRP that may qualify for CEP awards. The VICC GI SPORE DRP uses an established and highly effective procedure to solicit applications from investigators at Vanderbilt, MMC, and TSU. Internal and external researchers, including members of the GI SPORE External Advisory Board (EAB), review applications using the NIH 9-point scoring system. External reviewers will be selected by Dr. Peek and members of the DRAC based on expertise. Reviewers evaluate scientific merit and the likelihood of the project to support current GI SPORE activities, obtain extramural funding, and/or lead to future GI SPORE projects. The administrative core solicits the reviews, provides all reviewers with the application and score sheet, collects and collates the reviews, and forwards these to Dr. Peek and the DRAC for final decisions on support. We obtain three reviews for each application and have applicants give oral presentations to the DRAC prior to funding decisions. DRP attracts early-career investigators into GI cancer research, high-risk/high-gain projects, and projects that apply novel technologies to GI cancer research. Thus, the VICC GI SPORE DRP offers the opportunity for new directions of study that may be of higher risk, but also have a significant chance for reward, including independent funding and additional projects that may form the basis of the next competing renewal.
Career Enhancement Program
Program Director
Karen M. Winkfield, M.D., Ph.D.
Specific Aims
The goal of the Vanderbilt-Ingram Cancer Center (VICC) SPORE in Gastrointestinal (GI) Cancer Career Enhancement Program (CEP) is to provide individuals with the mentorship and collaborative interactions necessary for them to have successful and independent careers in translational GI cancer research. We have a multi-faceted and multi-layered plan for selecting and mentoring exceptional physicians and scientists to advance careers in GI cancer research and care. The goal is to provide CEP recipients with both an integrated, multi-disciplinary environment and an individualized mentored research experience that facilitate the development of outstanding research programs and successful academic careers.