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.
The University of Texas at San Antonio (UT San Antonio) was recently awarded a $10 million program project grant from the National Cancer Institute to investigate the connections between APOBEC mutagenesis and cancer. The program is the only National Cancer Institute-funded program specifically targeting APOBEC.
Program leader Reuben Harris, PhD, a Howard Hughes Medical Institute Investigator and professor and chair of the Department of Structural Biology at the Joe R. and Teresa Lozano Long School of Medicine, 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.”
Understanding APOBEC
APOBEC enzymes are deaminases that act on single-stranded DNA by removing an amino group from a molecule, resulting in the formation of keto acids and ammonia. Cytosine is one of the four nucleotide bases that are the building blocks of DNA. During the deamination process, cytosine is converted to uracil which can lead to mutations that accumulate over time. These mutations often occur after the initiation of cancer treatment and can lead to drug resistance and cancer recurrence.
The program’s central hypothesis is that inhibiting APOBEC will decrease tumor cell mutation rates and slow tumor evolution. Researchers are pursuing an “evolution-blocking” strategy that could one day be used in conjunction with current treatments to improve their effectiveness and long-term durability.
“Our long-term goal is to develop APOBEC inhibitors that are potent, selective and clinically useful,” Harris said.
Integrated, collaborative program
This grant renews and expands an already highly collaborative research program that’s continued for more than a decade with scientists from the UT San Antonio Health Science Center, University of Minnesota, University of California San Diego and other institutions across the country and around the world.
The program has already produced more than 100 publications across various projects, demonstrating the team’s aligned expertise and cohesive approach. Despite geographic distance, the team maintains strong connections through video conferences, workshops and collaboration and training opportunities for trainees.
Rather than just treating mutations, the scientists aim to transform cancer therapy by preventing mutations altogether, targeting two specific APOBEC enzymes. The team is building off previous successes including the development of powerful APOBEC inhibitors, a specialized antibody to track enzymes in tumors and the first mouse models to study APOBEC enzymes in action.
“Our teams are targeting the enzymes that fuel tumor mutation, opening the door to evolution-blocking agents that may revolutionize cancer therapy,” Harris said.
Cores and projects
Overall leadership for the program is shared by Harris and Douglas Yee, MD, professor of medicine and pharmacology at the University of Minnesota. Together, Harris and Yee will oversee three multidisciplinary projects supported by three service cores.
Core A, led by Harris and Yee, oversees administration and statistical support. Core B, led by Michael Carpenter, PhD, assistant professor and research specialist in the Department of Biochemistry and Structural Biology at UT San Antonio’s Health Science Center, will supply standardized APOBEC proteins and biochemical assays to support discovery and testing. Core C, led by Rommie Amaro, PhD, professor of biology at the University of California San Diego, integrates computational biochemistry, molecular modeling and bioinformatics to translate structural findings into biological insights.
Project 1, Structural Biology of DNA Deaminases in Cancer, is led by Hideki Aihara, PhD, professor of biochemistry, molecular biology and biophysics at the University of Minnesota. This project examines the structure of APOBEC enzymes and their atomic-level interactions with proteins, nanobodies, nucleic acids and small molecules.
Project 2, Chemical Biology of DNA Deaminases in Cancer, is directed by Daniel Harki, PhD, professor of medicinal chemistry at the University of Minnesota. This project drives the program’s chemical innovation, developing and refining inhibitors of APOBEC enzymes.
Project 3, Biology of DNA Deaminases in Cancer, is led by Harris with co-leads Yee and Harshita Gupta, PhD, MS, assistant professor and immunologist in the Department of Biochemistry and Structural Biology at UT San Antonio’s Health Science Center. This project explores how APOBEC enzymes drive cancer progression and resistance to therapy through studies at the cellular and whole organism levels.
Advisory boards and advocacy
Both internal and external advisory boards will provide scientific guidance and patient perspectives to the research team. The external board includes scientific experts as well as cancer survivors and patient advocates who play key roles in scientific review as well as public outreach. This unique group will help communicate scientific progress to the communities they serve, including South Texas.
Global collaboration and impact
The program also includes dozens of national and international collaborations that expand the program’s reach into translational impact. Together, this multidisciplinary team is advancing one of the most promising frontiers in cancer research by targeting the mutation process itself.
“By targeting APOBEC, we’re tackling one of cancer’s most persistent engines of change in cancer,” Harris said. “This could fundamentally alter how we think about and clinically manage long-term treatment.”