Direct MYC Inhibitor Passes First Clinical Test

The first direct inhibitor of MYC appears to be safe, with signs of antitumor activity in patients with advanced solid cancers, according to first-in-human data presented at the EORTC-NCI-AACR (ENA) Symposium on Molecular Targets and Cancer Therapeutics, held October 26–28 in Barcelona, Spain.

The 22-person MYCure trial found that the drug, a cell-penetrating peptide known as OMO-103 (Peptomyc), triggered mostly manageable infusion-related drug reactions, with eight of 17 evaluable patients experiencing stable disease, including one with a salivary gland tumor who's still receiving treatment after 15 months. No participants had partial or complete responses.

With respect to c-Myc drug development, “this is a milestone,” said Michael Duffy, PhD, of University College Dublin in Ireland, a clinical biochemist who studies anti-MYC therapeutics and who was not involved in the study. Now that the first MYC inhibitor appears to have passed its initial clinical test, Duffy expects others to soon follow. “There's momentum building,” he said.

OMO-103 has had a long road to the clinic. Laura Soucek, PhD, of the Vall d'Hebron Institute of Oncology (VHIO) in Barcelona, designed the drug more than 20 years ago as a tool with which to probe MYC function.

A transcription factor that orchestrates cancer-promoting signaling across myriad cellular pathways, MYC long eluded targeting owing to its lack of a binding pocket—needed for small-molecule therapeutics—and its nuclear location, which makes it inaccessible to antibody-based approaches. Soucek's drug, a c-MYC–derived mutant miniprotein acting as a dominant negative form of the protein, was a clever work-around. The 90 amino acid polypeptide, originally called Omomyc, silenced MYC in two ways: It dimerized with its target, thereby sequestering MYC from DNA, and it occupied MYC-target gene sites, resulting in transcriptional inhibition.

In 2014, Soucek created Peptomyc to advance a clinical-grade version of Omomyc, rebranded as OMO-103, into human trials.

At the ENA Symposium, MYCure lead investigator Elena Garralda, MD, of VHIO, described the results of a gene expression analysis showing that the therapy blunted MYC-driven transcriptional programs in patient tissue samples, with the gene changes proving most pronounced among trial participants who achieved stable disease on therapy.

That is “proof of target engagement with a shutdown of the MYC signature,” Garralda said. Others, however, viewed the findings with more caution.

Sarki Abdulkadir, MD, PhD, the founder of Vortex Therapeutics, a start-up developing analogues of a MYC inhibitor discovered in his laboratory at Northwestern University's Feinberg School of Medicine in Chicago, IL, called the findings “encouraging.” But he stressed the need for trial investigators to show whether OMO-103, which has a relatively short half-life and poor tissue distribution properties, truly reaches the nucleus of tumor cells and sufficiently inhibits MYC to sustain therapeutically meaningful benefits.

The role of antitumor immunity is not entirely clear either. In addition to the tumor cell–intrinsic influences of MYC inactivation, OMO-103 may be reversing some of MYC's immune-suppressive effects. Or, as Chi Van Dang, MD, PhD, of the Ludwig Institute for Cancer Research in New York, NY, pointed out, the modified peptide may be promoting nonspecific immune effects that ultimately aid in cancer control. “There's hope that it's targeting MYC,” Dang said, “but I would still put a big question mark” around that conclusion.

Soucek, also Peptomyc's CEO, is currently investigating the contribution of immune reprogramming to OMO-103's mechanism of action. Her team is also planning its next clinical steps, which could include combination studies with different standard-of-care treatments, she said. –Elie Dolgin

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.