A colorectal cancer research team led by Robert Coffey, MD, has received a prestigious Specialized Programs of Research Excellence (SPORE) grant renewal totaling $12.6 million from the National Cancer Institute (NCI) for a five-year period.

The grant marks ongoing funding of the GI SPORE awarded to Coffey’s team, which dates back to its inception at the Vanderbilt-Ingram Cancer Center in 2002. Currently, Vanderbilt-Ingram is one of only four cancer centers in the United States with GI Cancer SPORE funding. The team has made numerous discoveries over the past 23 years, and it plans to build upon those achievements with the goal of “drugging the undruggable.”

Applications for SPORE funding are intensely competitive. SPORE grants are highly sought after because they show that a cancer center demonstrates scientific excellence, promotes collaboration, maintains robust research programs and merits substantial funding — factors that are key determinants for an NCI designation as a Comprehensive Cancer Center.

“Our success is built upon clinical and basic investigators working closely together with patient advocates,” said Coffey, Ingram Professor of Cancer Research, professor of Medicine and of Cell and Developmental Biology, and co-director of the Epithelial Biology Center.

Coffey, the grant’s principal investigator, is joined by clinical co-leaders, basic science co-leaders, and patient advocates in pursuing three projects that are aimed at targeting three mechanisms of colorectal cancer progression: immune exclusion, MYC activation, and Wnt pathway activation. Each project has an embedded patient advocate to ensure that each project is focused on its translational goal.

“Securing SPORE funding is an achievement to be recognized, but having a program funded for 23 years is truly outstanding,” said Ben Ho Park, MD, PhD, the Benjamin F. Byrd Jr. Professor of Oncology and director of Vanderbilt-Ingram. “Congratulations go to Dr. Coffey, the principal investigator, and to the entire research team for a job well done. With this grant renewal, they are building upon years of rigorous and innovative research and are making great progress towards developing new therapies for gastrointestinal cancers that are recalcitrant to current treatment modalities.”

The team dedicated to the project of overcoming immune exclusion in microsatellite stable colorectal cancer includes clinical co-leader, Jordan Berlin, MD, associate director for Clinical Research at Vanderbilt-Ingram, Cornelius Abernathy Craig Professor of Medicine and director of the Division of Hematology and Oncology, along with basic science co-leaders Coffey and Ken Lau, PhD, professor of Cell and Developmental Biology and of Surgery and director of the Center for Computational Systems Biology.

Immunotherapies such as immune checkpoint blockade inhibitors have proven effective for a number of cancers, including a subset of colorectal cancer, but not for the 85% to 90% of colorectal cancers that are deemed microsatellite stable. The team will launch a clinical trial to see if an investigational drug can spur response in microsatellite stable colorectal cancers when combined with the immunotherapy drug pembrolizumab.

The investigators will also determine whether response can be tracked by monitoring proteins associated with plasma supermeres, novel nanoparticles discovered by the Coffey lab.

The team dedicated to targeting MYC is led by clinical co-leader, Kristin Ciombor, MD, MSCI, co-leader of the Gastrointestinal Cancer Research Program at Vanderbilt-Ingram, Ingram Associate Professor of Cancer Research and associate professor of Medicine. The basic science co-leader is William Tansey, PhD, associate director for Shared Resources and co-leader of the Genome Maintenance Research Program at Vanderbilt-Ingram, Ingram Professor of Cancer Research and professor of Cell and Developmental Biology.

Overexpression of the MYC gene is common in colorectal cancer, and the team will delve into whether a site on the protein WDR5 that plays a role inMYC action can be targeted for therapeutic benefit for patients with unresectable colorectal cancer. The investigators will lead a clinical trial to investigate the tolerability and antitumor efficacy of an experimental therapy developed by Stephen Fesik and Tansey in the last cycle of the SPORE award.

The team developing an inhibitor drug for the Wnt pathway is led by clinical co-leader, Cathy Eng, MD, co-leader of the Gastrointestinal Cancer Research Program at Vanderbilt-Ingram, David H. Johnson Professor of Surgical and Medical Oncology and professor of Medicine, along with basic science co-leaders Stephen Fesik, PhD, the Orrin H. Ingram II Professor of Cancer Research and professor of Biochemistry, Pharmacology and Chemistry, and Ethan Lee, MD, PhD, professor of Cell and Developmental Biology and of Pharmacology.

Activation of the Wntpathway is a characteristic of colorectal cancer and has been notoriously hard to target without adverse toxicities. The Wnt-focused team will be developing a first-in-class inhibitor that could revolutionize the landscape of treatment for colorectal cancer due to its dependence on Wnt activation for establishment and progression.

The GI SPORE grant also cultivates future scientific advancement through the Career Enhancement Program at Vanderbilt-Ingram, which recruits young investigators and helps them develop into independent researchers. Participants can apply for seed funding — small grants that help them establish the basis for research achievements that merit additional funding.

These programs are led by Karen Winkfield, MD, PhD, associate director for Community Outreach and Engagement at Vanderbilt-Ingram, Ingram Professor of Cancer Research and professor of Radiation Oncology, and Richard Peek, MD, the Mina Cobb Wallace Professor of Immunology and professor of Medicine and Pathology, Microbiology and Immunology.

Overall, this grant is a large accomplishment that shows the importance of team science and collaboration of basic and clinical leaders together with patient advocates to propel advances in the diagnosis and treatment of GI malignancies.

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