Written by: Claire Kowalick
More than 70% of cancers — including breast, bladder, cervical and lung cancer — show evidence of mutations linked to a group of enzymes called apolipoprotein B mRNA-editing enzyme catalytic polypeptides, or APOBEC.
“APOBEC mutagenesis is the second-largest source of mutation in cancer and, importantly, the largest one we can do something about. If we inhibit these enzymes, we could slow tumor evolution, reduce drug resistance and make existing cancer therapies more effective,” said Reuben Harris, PhD, Howard Hughes Medical Institute Investigator, professor and chair of the Department of Structural Biology at the Joe R. and Teresa Lozano Long School of Medicine at the University of Texas at San Antonio (UT San Antonio).
Harris received a $10 million grant from the National Cancer Institute (NCI) this fall to expand a collaborative research program focused on APOBEC. His team, alongside partners at the University of Minnesota, University of California San Diego and other institutions worldwide have been studying APOBEC-driven mutations in cancer for more than a decade. The program is the only NCI-funded program dedicated solely to this area.
What is APOBEC?
APOBEC is a family of enzymes that can alter DNA as part of the body’s natural immune defense. Many APOBEC enzymes help fight viral infections by introducing mutations into viruses which can stop them from replicating.
However, these enzymes can also act on the cell’s own DNA, particularly when DNA is temporarily exposed during normal processes like replication and repair.
Dysregulated APOBEC activity can lead to accumulation of DNA mutations that contribute to cancer development. Over time, this can drive tumor evolution, leading to drug resistance and cancer recurrence.
Goal of the program
The program aims to develop ways of inhibiting APOBEC activity and limit mutations that allow tumor evolution. Researchers hope this strategy could one day be used alongside existing treatments to improve long-term outcomes.
“Our long-term goal is to develop APOBEC inhibitors that are potent, selective and clinically useful,” Harris said.
Changing cancer treatment
Rather than targeting mutations after they occur, the team proposes a way to prevent them from forming by targeting two key APOBEC enzymes.
The effort builds off earlier successes including the development of experimental APOBEC inhibitors, a tool to track enzymes in tumors and the first animal models to study APOBEC enzyme activity.
Core teams and project leads
The program is co-led by Harris and Douglas Yee, MD, professor of medicine and pharmacology at the University of Minnesota. Together, they oversee three multidisciplinary research projects supported by three specialized cores providing administrative coordination, biomedical resources and computational modeling.
Project teams are studying APOBEC enzymes at multiple levels — from atomic structure to cellular behavior and whole-organism biology — to better understand how they drive cancer progression and treatment resistance.
Advisory boards, including one made up of cancer survivors and patient advocates, help guide the program and communicate its progress to the communities they serve.
Why it matters
Along with the core research team, the group is partnering with dozens of national and international collaborations to expand their reach into translational impact. Together, they are advancing one of the most promising frontiers in cancer research with a focus on 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.”