The Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation has awarded a $1 million grant to support research at Vanderbilt aimed at dramatically expanding the efficacy of immunotherapy for colorectal cancer.
Currently, only people with microsatellite-high colorectal cancer, which accounts for about 10% of patients, respond to immune checkpoint inhibitors, but Vanderbilt researchers have discovered proteins that could be targeted to potentially benefit the other 90%. The work is the latest collaboration between Robert Coffey, MD, Ingram Professor of Cancer Research, and Ken Lau, PhD, professor of Cell and Developmental Biology, to understand the mechanisms of colorectal cancer. It builds on recent discoveries by their research teams.
Notably, the researchers identified three immune exclusion biomarkers associated with the 90% of colorectal cancer cases that are microsatellite stable and have a paucity of CD8 T cells. These three genes, DDR1, TGFBi and DPEP1, take part in cancer cell packaging of proteins into nanoparticles, including small extracellular vesicles and newly discovered “supermeres,” which are secreted to regulate the extracellular microenvironment.
Coffey’s research team discovered supermeres and reported their study in the journal Nature Cell Biology on Dec. 9, 2021. Two years later, in another study published Dec. 7, 2023 in the journal Cell, Coffey and Lau reported the role of the immune exclusion genes in human colorectal cancer.
The Kleberg Foundation will support the next step in their research. Coffey and Lau plan to uncover the mechanistic underpinnings of supermeres in the tumor microenvironment, look for other immune exclusion biomarkers, and evaluate the efficacy of immunotherapy when immune exclusion proteins are targeted.
DDR1 will be targeted with the antibody PRTH-101, which binds to and blocks DDR1. VUMC is a phase 1 and phase 2 clinical trial site testing PRTH-101. The researchers also have access to a TGFBi-neutralizing antibody being developed for clinical trials. DPEP1 will be targeted by an inhibitor that is already approved by the Food and Drug Administration to block the protein’s enzymatic activity, while clinical trials are underway to study the drug’s effect on the protein’s receptor function.
The work will involve multiomics analysis, machine learning, patient-derived organoids and other research technologies. The overarching goal is to find a way to transform “immune cold” tumor molecules into “immune hot” ones, so that immunotherapy can unleash CD8 T cells to kill cancer cells.
“We are proud to continue investing in novel cancer research at Vanderbilt-Ingram Cancer Center,” said Helen Alexander, president of the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation. “Our longtime partnership has yielded many advancements in therapies for cancers of all types; this latest grant will support crucial next steps in Vanderbilt-Ingram’s quest to find more effective treatments for historically untreatable colorectal cancers.”
The Foundation, which is based in Texas, funds medical research that is innovative and groundbreaking with distinctive and novel approaches.
The discovery of the supermere, a nanoparticle that has tumor-promoting properties, was built upon foundational work in extracellular vesicles called exosomes by Vanderbilt researchers. In a study published in the journal Cell, they described optimized methods for isolating and characterizing exosomes. Coffey, who has investigated colorectal cancer for more than 25 years, is the co-director of the Epithelial Biology Center and the principal investigator of Vanderbilt-Ingram Cancer Center Gastrointestinal Specialized Programs of Research Excellence, which focuses on colorectal cancer.
“The incredible generosity of the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation will allow us to delve deeply into the basic mechanisms by which DDR1 and TGFBi act and to translate these insights clinically,” said Coffey, who is a professor of Medicine and of Cell and Developmental Biology.
Coffey leads a lab at Vanderbilt University Medical Center, while Lau leads another lab at Vanderbilt University. Lau’s lab develops and applies computational approaches to high-content data generated by single-cell and spatial technologies to understand epithelial tissue function and organization. Lau is the new director of the Center for Computational Systems Biology.
“I am deeply grateful to the Foundation for their generous support of high-risk research that bridges basic and translational sciences. Vanderbilt provides the ideal collaborative environment to advance this important, interdisciplinary work,” said Lau, who is also professor of Surgery.
The Foundation has supported cancer research at Vanderbilt for more than 50 years, starting with a gift in 1973 to the A.B. Hancock Jr. Memorial Laboratory for Cancer Research when it was newly established. To date, the Foundation has provided nearly $26 million in support.
