Researchers hypothesized that to reverse DNA methylation, there would need to be chronic, low-doses to both enable patient tolerance and prevent the abnormality from returning. It was unclear, however, how to give the combination over long periods of time in the clinic.
“The big surprise we found while studying the NSCLC cell culture was that, in addition to augmenting the tumor induction for immune signaling through an interferon generating response that we knew the DNA demethylating agent itself can produce, the HDAC inhibitor not only augmented this but was occurring with down-regulation of signaling, best seen with both drugs, for the very important tumor oncogene, CMYC,” Dr Baylin said.
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“MYC was found to directly antagonize the up-regulation of the tumor immune signaling. So we were getting a ‘two-fer,’ because we were down-regulating MYC, which was fighting against us, and simultaneously allowing for better up-regulation of the tumor immune signaling.”
Clinical Implications
The SU2C Catalyst project has just started enrolling patients with a goal of “augmenting the performance of immune checkpoint therapy in these patients with NSCLC. It is possible that many more patients may respond initially to the combination, and if we see this, we will also work in the future on whether we can reverse resistance,” Dr Baylin said.
Presuming the initial 1-year outcomes are favorable, “that would help this combination rise to the top in terms of getting approval for a registration trial,” he said. A “best case” scenario would have this therapy in a registration trial within 2 years, but Dr Baylin acknowledged there are too many variables at this point to predict that far into the future.
“We will also retrospectively examine whether there’s an aggregation of those patients who respond to specific categories of gene mutations in their tumors. Do we improve outcomes across the spectrum of the mutational burden? These are questions we need to answer,” he said.
Reference
- Topper MJ, Vaz M, Chiappinelli KB, et al. Epigenetic therapy ties MYC depletion to reversing immune evasion and treating lung cancer. Cell. 2017;171(6):1284-1300.e21. doi: 10.1016/j.cell.2017.10.022
- 10 SU2C catalyst clinical trials launched [news release]. Philadelphia, PA: Stand Up To Cancer; October 12, 2017. http://www.standuptocancer.org/press_release/view/10_su2c_catalyst_clinical_trials_launched. Accessed December 2017.
