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Epigenetic Therapies May Prime Tumors to Better Respond to Other Treatments, AACR Speakers Say

ATLANTA (GenomeWeb) – Epigenetic therapies may help push solid tumors to be more responsive to other forms of treatment, according to speakers at this year's American Association for Cancer Research meeting here.

While there are no approved epigenetic therapies for solid tumors in the US, there are about half-a-dozen that are approved for use in hematological cancers and they have been under investigation for solid tumors like colorectal, lung, and breast cancers. Though studies of epigenetic therapies on their own for these tumor types have largely been disappointing, the speakers noted that there have been hints that epigenetic therapies could be used to prime these solid tumors to better respond to other types of therapies.

In general, the allure of epigenetic drugs is to target the global epigenetic dysregulation that occurs in cancer to restore the expression of, for instance tumor suppressor genes, and early research indicates epigenetically silenced genes could be reactivated, the University of Pittsburgh Cancer Institute's James Herman said during a session Tuesday on advancing epigenetic therapies.

Azacitidine, marketed by Celgene as Vidaza, was the first epigenetic drug to be approved in the US, in 2004, to treat myelodysplastic syndrome, and there are now two DNA methyltransferase (DNMT) inhibitors and five histone deacetylase (HDAC) inhibitors that have been approved, all for hematological malignancies.

Work in hematological settings has shown, as the Yale School of Medicine's Nita Ahuja noted during her presentation, that the effects of epigenetic drugs could take time — even months — until they are apparent. Additionally, she said that drugs like azacitidine and decitabine have short half lives of less than an hour, which could have implications for their use treating solid tumors that have higher tumor burden.

Herman added that initial studies suggest epigenetic drugs have the potential to make tumor cells sensitive to other cytotoxic agents as they can restore silenced functions like apoptosis.

In 2011, he and his colleagues reported in the journal Cancer Discovery on a phase I/II trial in which they treated patients with recurrent metastatic non–small cell lung cancer with a combined epigenetic therapy of the DNMT inhibitor azacitidine and HDAC inhibitor entinostat to pursue that hypothesis. Overall, Herman said that they found that some patients had good initial responses, but most patients progressed.

However, some patients survived more than a year on this third-line therapy.

Herman noted during his talk, though, that many of the patients had been referred back to their local oncologists for additional chemotherapy, and some patients — even those who had no response to the epigenetic therapies — had very long survival with treatments that usually aren't linked to long survival.

"[This] suggested that the epigenetic therapies may have changed the phenotype of the tumors in such a way that they were now responsive to more conventional chemotherapy," Herman said.

This potential priming effect, he and the other speakers said, is now being further explored in not just lung cancer, but other solid tumors, as well.

For instance, following work in cell lines and mouse models, Ahuja and her colleagues sought to examine whether priming patients with guadecitabine, a DNMT inhibitor that's designed to have a longer half life, could reverse resistance to the chemotherapy drug irinotecan. In a phase I dose-escalation clinical trial, published in Clinical Cancer Research this past December, Ahuja and her colleagues examined the safety and tolerability of guadecitabine in conjunction with irinotecan in metastatic colorectal cancer. While the study wasn't intended to examine responses, Ahuja said during her talk that they did note decreased disease burden among some patients with increasing number of drug cycles.

Based on this, they have now started a randomized phase 2 study of irinotecan and guadecitabine versus regorafenib or TAS-102.

Similarly, Nancy Davidson from the Fred Hutchinson Cancer Research Center said epigenetic therapies are being examined in breast cancer as a means of overcoming hormone resistance. She noted that they've seen this in both cell lines and animal models, and though a randomized phase 2 trial of an aromatase inhibitor with or without entinostat showed no difference in progression-free survival, the combination treatment was linked to an increase in overall survival.

Following on this, Davidson noted there are two phase 3 clinical trials, including one of exemestane with or without entinostat that was recently reported. As in the previous trial, there was no difference in progression-free survival. But Davidson added that the overall survival results are still pending.

And in lung cancer, Herman added that a randomized phase II study of epigenetic priming with azacitidine and entinostat prior to treatment with the PD-1 inhibitor nivolumab, marketed by Bristol-Myers Squibb as Opdivo, is underway to gauge its effect on response. This shift toward immunotherapies, he noted, is due to immunotherapy becoming the go-to treatment for patients with non-small cell lung cancer.

"We hope this will now look at the possibility of restoring immune response to those who were previously treated with PD-1 therapies," Herman said.