Colorectal Cancer

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 instability-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. Vanderbilt University Medical Center 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.”