Inhibition of Myc Protein Zaps Lung Tumors

Turning off a key protein eliminates lung tumors in mice, at least during treatment, according to new research published in the journal Genes & Development. Inhibition of Myc, a protein essential for lung tumors driven by a mutation in the KRas gene, resulted in regression of all tumors. Repeated treatments were found to be safe and effective.

High or aberrant Myc activity is associated with many different cancers, including cervical, breast, colon, lung, and stomach cancers. As a transcription factor, Myc is involved in cell proliferation, differentiation, and programmed cell death, or apoptosis. Researchers have been drawn to study Myc because it acts like a bottleneck in cancer pathways, integrating growth signals and relaying them to thousands of target genes. This unique position in cancer signaling makes Myc an attractive target for therapy.

The new study, led by Laura Soucek of the University of California San Francisco and the Vall d’Hebron Institute of Oncology in Barcelona, Spain, made use of a previously developed method to block Myc. The Myc-inhibiting mutant protein, called Omomyc, induced regression of lung tumors, but did not target normal tissue, according to earlier research by Soucek and colleagues. They wanted to extend their work to find out more about the Omomyc mechanism and whether it could help mice with lung tumors live longer.

Lung tumors were completely eradicated when Omomyc expression was induced in the experimental mice via an antibiotic in their drinking water. When the Omomyc treatment was discontinued after 4 weeks, the tumors relapsed, but they were fewer in number and no new tumors appeared. Omomyc induction extended the overall survival of the mice.

Because cancer relapse is often associated with the development of resistance to therapy, the researchers also wanted to test whether the regrown tumors had acquired resistance to Omomyc. When the gene therapy was reinduced, all tumors—around 200 in each mouse—again regressed. After two rounds of treatment, only roughly 11% of tumors reappeared. Mice were maintained on a schedule of 4 weeks of Omomyc treatment followed by 4 weeks of rest for over a year. After eight cycles of this therapy only two tumors were found. The mice appeared healthy, maintained their weight, and showed minimal side effects during the on-and-off treatment.

“The most important finding was that there were no signs of resistance to treatment,” Soucek says. “One year of life in a mouse is equivalent to almost 40 human years. The fact that the results are maintained over time, that there is no tumor relapse and no resistance, suggests that Myc-targeted therapy may offer an unprecedented way forward.”

To confirm that acquired resistance did not, in fact, emerge, the researchers tested the effects of Myc inhibition while suppressing another protein, a cell cycle regulator called p53. “Without p53, a tumor can accumulate a large number of mutations,” Soucek says. “If there were any chance of a mutation appearing and managing to resist Myc inhibition, this would have happened in the absence of p53.”

Under these p53-suppressing conditions, Omomyc induction again cleared all tumors, but this process was somewhat slower. The researchers concluded that the tumor-killing effect of Myc inhibition is independent of p53, though p53 does facilitate the effect.

Because Myc is such an important regulator of many genes, its long-term inhibition could have serious side effects. Repeated short-term inhibition of Myc, however, does contain lung tumors and crucially eludes acquired resistance and maintains treatment efficacy over time in the preclinical mouse model.

Dr. Soucek says next steps include making Myc inhibition, “feasible from a pharmacological point of view, so that it can be administered, and done so safely. This will be the last step before designing clinical trials with Myc inhibitors.”