The big news in epigenetics this week is a two-drug epigenetic combo that shows results as good as the best FDA-approved chemotherapy in fighting non-small cell lung cancer, which accounts for about 80 percent such cancers. But missing from a lot of the mainstream accounts, the related study took a look at blood-based biomarkers, finding that they might serve as good indicators of whether a patient’s responding to treatment.
Conducted by Johns Hopkins University’s Rosalind Juergens and colleagues, the phase I/II trial appears to be the most successful study of an epigenetic treatment of a solid tumor. I say this all the time, but keep in mind we’re still talking about a small sample size–the researchers studied 45 patients taking the DNA methylase inhibitor 5-azacytidine and the histone deacetylase inhibitor entinostat. Still, the patient survival numbers are significant, and when we look at those who later underwent chemotherapy, they get even better.
Of course, even when lung cancer trial results are good, they’re still quite grim. The patients’ median survival was 6.4 months, compared to 6.7 months for patients treated with the approved chemotherapy, erlotinib. (Patients receiving a placebo have a median survival of 4.7 months.) The patients who finished at least one cycle of treatments had a median survival of 8.6 months.
Of patients those who did two treatment cycles, one person had a complete response for 14 months, another showed a partial response for two months. The disease stabilized in ten patients, while 22 had progressive disease. The rest of patients didn’t get through one cycle of treatment.
Here’s where that second punch comes in. The idea–not proven yet–is that re-igniting anti-cancer activity in epigenetically silenced genes is only part of the story. In chemo-treated cancers, there’s a core of tough-to-kill cells that may protect themselves through epigenetic means. Reset the transcription machinery, and that goes away. Now, all of the patients in this trial had been treated previously. So when 19 seek later therapy, and four of them have “major objective responses,” it’s a good turn of fortune.
Now to the diagnostic potential. The researchers found four DNA markers that appear to be able to show when this epigenetic therapy is going to work–80 percent of patients (eight of ten) who showed less methylation at four gene promoters after treatment also had stable disease or an objective response. Only one-fourth of the patients who lacked that methylation signature still showed stable disease after a cycle of treatment.
And a good diagnostic shouldn’t require hard-to-get samples, so this part’s nice. Lacking tumor samples, the investigators tested tumor DNA in blood samples they took before and after the treatment cycles, looking at the methylation status of APC, RASSF1a, CDH13, and CDKN2a. When they’re hypermethylated, that’s a bad sign for patient prognosis–if two of these four genes’ promoters are marked, the disease is much more likely to recur.
Apparently, it might also be a good way to tell whether a patient’s going to benefit from this particular epigenetic treatment–and other epigenetic treatments too, with any luck. Manel Esteller, editor of the journal Epigenetics, writes in a commentary article accompanying this study in Cancer Discovery that future studies investigating DNMT inhibition might want to use similar biomarkers to see how they pan out.
[The really well-faked face punch photo by Flickr user .A.A is used here under a Creative Commons license.]
Juergens, R., Wrangle, J., Vendetti, F., Murphy, S., Zhao, M., Coleman, B., Sebree, R., Rodgers, K., Hooker, C., Franco, N., Lee, B., Tsai, S., Delgado, I., Rudek, M., Belinsky, S., Herman, J., Baylin, S., Brock, M., & Rudin, C. (2011). Combination Epigenetic Therapy Has Efficacy in Patients with Refractory Advanced Non-Small Cell Lung Cancer Cancer Discovery DOI: 10.1158/2159-8290.CD-11-0214