More than 70% of all cancers are impacted by mutations caused by a group of DNA-editing enzymes that drives tumor growth and drug resistance. The apolipoprotein B mRNA-editing enzyme catalytic polypeptide, or APOBEC, family, is a dominant factor in many cancers including bladder, breast, cervical, head and neck, and lung.
Researchers at UT Health San Antonio, the academic health center of the The University of Texas at San Antonio (UT San Antonio) were recently awarded a $10 million program project grant from the National Cancer Institute to investigate the connections between the APOBEC mutagenesis and cancer. The program is the only National Cancer Institute-funded program specifically targeting APOBEC.
Reuben Harris, PhD, a Howard Hughes Medical Institute Investigator and professor and chair of the Department of Biochemistry and Structural Biology at the Joe R. and Teresa Lozano Long School of Medicine at UT San Antonio, leads the program and has devoted much of his career to uncovering how APOBEC enzymes contribute to mutations in cancer and how to stop them.
“APOBEC mutagenesis is the second-largest source of mutation in cancer and, importantly, the largest actionable one,” Harris said. “If we can inhibit these enzymes, we can slow tumor evolution, reduce drug resistance, and make existing cancer therapies more effective.”
APOBEC enzymes alter single-stranded DNA by converting cytosine into uracil, a change that creates mutations. Over time, these mutations can accumulate, especially during cancer treatment, contributing to cancer recurrence, drug resistance and metastasis.
The program’s core hypothesis is that blocking APOBEC activity will reduce tumor mutation rates and slow cancer’s evolution. By pursuing this “evolution-blocking” strategy, researchers aim to strengthen current therapies and improve their long-term effectiveness.
“Our long-term goal is to develop APOBEC inhibitors that are potent, selective and clinically useful,” Harris said.
This renewed grant strengthens a long-standing, highly collaborative program uniting scientists from UT San Antonio, the University of Minnesota and UC San Diego. Over the past decade, the team has produced more than 100 publications, supported by consistent communication, shared training, and seamless collaboration across institutions.
Building on major breakthroughs — including potent APOBEC inhibitors, a specialized antibody to track the enzymes in tumors, and the first mouse models to study APOBEC activity — the researchers aim not just to treat cancer mutations but to prevent them altogether by targeting APOBEC. This approach represents a potential shift in how cancer therapy is designed and delivered.
“Our team is targeting the enzymes that fuel tumor mutation, opening the door to evolution-blocking agents that may revolutionize cancer therapy,” Harris said.
The program is powered by a network of collaborators, extending its ability to turn laboratory discoveries into real clinical progress. This multidisciplinary and highly collaborative approach is critical because APOBEC-driven mutations fuel many different types of cancer worldwide.
“By targeting APOBEC, we’re tackling one of cancer’s most persistent engines of change,” Harris said. “This could fundamentally alter how we think about and clinically manage long-term treatment.”
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