Translational Research Project Explores Enzymes' Cancer Role

With support from the National Cancer Institute, The Children’s Hospital of Philadelphia Matthew D. Weitzman, PhD, is studying the relation of a family of proteins to cancer. The proteins in question, the ponderously named APOBEC3 (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3) family of deaminases, play a key role in defending against viruses, but are also being investigated as a possible cause of cellular DNA damage that can lead to cancer.

Dr. Weitzman has been working closely with Abby Green, MD, currently an instructor in Pediatric Oncology. In July of 2014 Dr. Green received a grant of her own to study APOBECs — a two-year Young Investigator Award from Alex’s Lemonade Stand Foundation (ALSF).

Drs. Weitzman and Green’s work seeks to understand better how these enzymes disrupt the genome and cause mutations, and how APOBECs (pronounced AE-POE-BECK) are regulated. Their broad goal is to discover and develop new treatment methods based on a deeper understanding of the relationship between these enzymes and cancer cells. For her part, Dr. Green’s ALSF grant funds an investigation into whether the DNA mutations caused by APOBECs make cancer cells more receptive to drugs.

The work builds on recent investigations into the enzymes’ relation to cancer by Dr. Weitzman and others. In 2011 he published a paper in EMBO Reports with colleagues from the Salk Institute showing that some APOBECs could cause genomic instability. His five-year R01 grant from the National Cancer Institute seeks to build on the EMBO Reports work.

“The grant is asking basically can we show that these enzymes actually cause those [mutational] signatures and fulfill what is predicted retrospectively,” Dr. Weitzman said. “The next questions address what regulates activity, what makes sure it doesn’t happen normally, what are the modifications, what are the interactive proteins, where’s it expressed and localized in the cell, and other fundamental questions about these potentially harmful enzymes.”

Potentially Paradoxical Proteins

Though APOBECs have been the focus of increased attention in recent years, they remain poorly understood. How, some have wondered, could enzymes that perform an immune function also induce cancer-causing mutations? A review of these enzymes offered a possible answer: age. In their Intrinsic Immunity, Current Topics in Microbiology, the University of Minnesota’s Reuben S. Harris, PhD, and Eric W. Refsland, PhD, address the question of how, and why, enzymes whose primary role is to fight viruses could be a cause of human cancer.

“An attractive explanation for this apparent conundrum may be that [APOBECs’] innate function is important early in life and for the health of the species, for instance, in germ cells or early development, whereas the toll of cancer is not imposed in most instances until after the reproductive years,” they note. “In any event, much more work is now justified on APOBEC3B and its role in breast and, potentially, other human cancers.”

Hence the importance of studies like Drs. Weitzman and Green’s. Dr. Weitzman pointed out that while cancer genome sequencing studies have revealed a great deal of information about how cancer arises, and discovered genes associated with certain cancers, they don’t necessarily provide the mechanism by which things happen.

“We want to bridge that gap,” said Dr. Green.

And though their study is mechanistic, greater knowledge of APOBECs’ role in causing cancer, and how this family of enzymes is regulated, could lead to diagnostic and therapeutic approaches in the future. “If we find that these APOBECs are involved in pediatric cancers, there may be a diagnostic role, or a therapeutic opportunity. We have lots of translational ideas, but we just have to get this first work done,” Dr. Green added.

Indeed, it is CHOP’s unique ability to pair laboratory researchers with clinicians like Dr. Green that allows investigators to think more translationally, Dr. Weitzman noted. He said that his work has really benefitted from the input and expertise of Dr. Green, who is the first clinician to work in his lab.

“CHOP has this ability to pair basic researchers with clinicians, and both sides stimulate each other to think together about translational ideas,” Dr. Weitzman said.