Friday, June 8, 2012

Epigentic Therapy


DNA methylation as a biomarker to detect and assess tumor growth is only one part of the cancer equation. New studies show the active role of epigenetic changes in development of a treatment of cancer. Traditionally, clinic treatments involve radiation, surgery or drug poisoning. The introduction of a class of drugs that target some proteins in the cancer pathway seems promising. These drugs are referred as "epi-drugs" in a study done by Juergens and colleages (11). Epi-drugs target the DNA methylation machinery such as inhibiting DNA methyltransferases (DNMTi). By interfering with the methylation, some cancer tumor suppressor genes will not be silenced, thus a epigenetic therapy. The patients whose specific genes were unmethylated responded well to traditional therapies such as radiation after the epigenetic therapy. The demethylation of those genes made the cancerous cells more susceptible to chemotherapy.

The study was an experimental design that tested the toxicity of the drugs and effects in terms of years of survival and the stabilization or nonprogression of the tumor. The article mentions a combined epigenetic therapy, implying that the patients that had recieved the epi-drug with the addition of another drug (inhibits HDACi, which affects histone deacetylases that play a role in transcription of genes). Azacitidine (inhibitor of methyltransferase) and entinostat (histone deacetylation) were the epi-drugs used in the study that involved 45 patients with refractory metastatic non-small call lung cancer (NSCLC). The reason that researchers decided to use a histone deacetylation was because with inhibitors of methyltransferases alone the re-expression of tumor suppressor genes were not expressed. HDAC influences gene expression and when used in combination of inhibitors of methyltransferases, gene expression is reactivated.

Within the experiment, there were 4 genes specifically targeted to de-methylate: CDKN2a, CDH13, APC and RASSF1a. It was correlated that "methylation of any 2 out of the 4 in a tumor conferred to a worse prognosis in patients with stage I lung cancer, similar to patients with stage III disease" (11). However before the effect of epi-drugs on overall survival, researchers had performed an experiment on the toxicity of the drugs on ten patients. 3 patients received 30 mg/m2/d and 7 received 40 mg/m2/d. All patients were given 7 mg/m2/d of entinostat at day 3 and 10 to ensure that demethylation will occur. Based on the observations of side effects such as low grade skin, fatigue, vomiting, constipation, anorexia, electrolyte disturbances and hyperglycemia from entionstat or azacitidine toxicity, the epi-drugs appear to be non-targeted. Traditional chemotherapies have these side effects as well, which lead to the question: are the epi-drugs working? In the results of the toxicity experiment, the 3 patients that recieved a lower dose did not experience dose-limiting toxicity. The maximal dosage of azacitidine was set at 40 mg/m (11).

As for the efficiency of the epi-drugs, 1 patient (out of 45) was observed to be responsive to chemotherapy for 14 months. Another patient was partially responsive for 8 months. Ten were observed to have a stabilized tumor (tumor did not grow) for at least 12 weeks. However, 22 were observed to have a progressive tumor after the epigenetic therapy. Overall, with the exception of 2 very lucky patients, the epi-drugs were not very efficient. This may be due to the fact that the epi-drugs do not target specific methyltranfserases. It also may be due to the fact that the cancerous cells may have adapted to the epi-drugs by over expressing methyltransferases, especially with a low dosage of epi-drugs (11).

However, this experiment targeted 4 genes for demethylation. DNA methylation biomarkers were used to assess the methylation of these genes though blood plasma DNA. In the figure, the red line shows patients with demethylation of 2 or more of the 4 targeted promoter genes. The blue line shows patients that did not indicate a change in hypermethylation of the 4 promoter genes.

Figure 9. Proportion progression Free

Figure 10. Proportion Surviving

From the proportion progressive-free, the patients who had demethylation of the genes were seen to have an overall higher percentage of "stabilized" methylation towards the end of the graph compared to the patients with no change in methylation of the 4 genes. For the proportion surviving, the patients who had demethylation of the genes have a longer "tail" for the amount of months of survival towards the end compared to the patients with stabilized methylation. DNA methylation biomarkers are able to aid in the progression of the tumor of the effects of the epi-drugs.
By inhibiting DNA methyltransferases, it has been observed to make the cancerous cells more sensitive to chemotherapy. Patients with demethylated genes had an overall survival. Another advantage of epi-drugs is the drugs are quite efficient in small doses. DNA blood plasma was used to measure the amount of de-methylation of the target genes. However, we are not sure if the de-methylation occurred at the tumor site. The epi-drugs' side effects indicate that the inhibition of DNA methyltransferases are non targeted. If the drugs are non targeted, how will we know for certain that the demethylating of target genes are from the tumor? Can we assume that those target genes are unique only to cancerous cells? More research is needed to answer these questions.
Low doses of epi-drugs are effective when given to patients. However, it worries me that the immune system or the cancerous cells may adapt to the epi-drugs. The immune system may destroy the epi-drug before it has reached its destination. The cancerous cells in response to the epi-drugs, may increase expression of DNA methyltransferase, rendering the drugs useless. A possible solution is to increase the amount of epi-drugs. However, increasing the amount of epi-drugs may do the patient more harm than good. Since the side effects of these drugs are similar to chemotherapy, one might as well suffer under chemotherapy which has yielded some certain positive effects on the cancer cells.


Juergens, R., Wrangle, J., Vendetti, F.P., Murphy S.C., Zhao, M., Coleman, B., et al. “A Combined Epigenetic Therapy Equals the Efficacy of Conventional Chemotherapy in Refractory Advanced Non-Small Cell Lung Cancer.” Cancer Discovery. (2011) 1:598-607.