Starting at conception, myriad gene-expression changes in human cells culminate in the 100 or so different types of tissue found in adults. We owe that genetic orchestration to epigenetic factors, such as the methyl groups that modulate gene activity when they bind to DNA.

Those factors are themselves regulated by proteins, primarily enzymes—and mutations in genes coding for those enzymes are common in human cancers. Vern and his team made several transition-state analogues against MTAP, an enzyme implicated in many cases of prostate cancer, head and neck cancer, lung cancer, and other solid tumors.

MTAP plays a crucial role in normal development. It’s a part of cells’ pathway that provides the methyl groups that regulate gene expression. Cancer cells rely on MTAP and other epigenetic enzymes to evolve from a single cell to a small tumor to a metastatic tumor, all of which have different gene expression patterns.

“Our MTAP inhibitors are intended to throw a monkey wrench into the developmental pathway of these cancers while causing none of the well-known side effects of cancer chemotherapy,” Vern says. “The idea is to have a nontoxic compound that slows or even halts the growth of tumors—keeping them small so they don’t progress to metatastic cancer, which is often fatal.”

Vern notes that these MTAP inhibitors have shown “tremendous promise” against human tumors implanted in mice. They’ve caused remission of head and neck cancer; reduced primary tumor growth and metastases in lung cancer; and significantly decreased the size of prostate tumors. No adverse effects were observed in mice. “We’re hoping for a big future for these compounds in cancer therapy,” he adds.

A recent discovery could expand the use of MTAP inhibitors. The gene that codes for the MTAP enzyme is deleted in 15 percent of all human cancers, which manage to survive without it. But as three teams of researchers reported in 2016, cancers lacking MTAP are highly vulnerable to attack, since their MTAP deficit makes them more dependent on other key enzymes, PRMT5 and MAT2A. Those findings were reported in the journal Science in February 2016 and March 2016, and in Cell Reports in April 2016. 

The therapeutic implications were clear: Find a drug that administers the coup de grace to MTAP, and the cancers all become more sensitive to PRMT5 and MAT2A inhibitors.

Several anti-PRMT5 drugs are now in clinical trials. The potential one-two punch, combining anti-PRMT5 drugs with Vern’s MTAP inhibitors, might defeat the other 85 percent of human cancers that retain their MTAP genes.

 —Larry Katzenstein