TARGETING EPIGENETIC ABNORMALITIES

June 21, 2010 (Barcelona, Spain) — Epigenetic abnormalities appear to be a new therapeutic target for a range of cancers. Low doses of demethylating agents used in combination appear to induce lung cancer cells to become less malignant, according to data from trials of advanced lung cancer patients.

Presenting his preliminary results here at the 15th Congress of the European Hematology Association (EHA), Stephen Baylin, MD, deputy director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland, explained evidence suggesting that, in preclinical studies, low, less toxic doses of 5-azacytidine (Vidaza, Celgene) and 5-aza-2'-deoxycytidine (Dacogen, Eisai), work by reprogramming tumor cells to revert to a less tumorigenic state. Full results have been submitted to a medical journal.

These drugs, used at much lower doses than when they were originally introduced, have been used in the preleukemic disease myelodysplasia since the 1990s, and are now approved by the US Food and Drug Administration (FDA) for this purpose. Now, low doses of these drugs are being combined with histone deacetylase inhibitors (HDACIs) in trials for myelodysplasia, acute myelogenous leukemia, and — very recently — for nonsmall-cell lung carcinoma, a solid tumor.

All of the above drug types produce epigenetic effects on the genome, Dr. Baylin explained, with 5-azacytidine and 5-aza-2'-deoxycytidine exerting DNA demethylating effects and HDACIs increasing histone acetylation.

"In our lab, we have found that you can use low doses of the 2 demethylating drugs together to boost gene function when followed by HDACIs; these combinations are in clinical trials," Dr. Baylin told Medscape Hematology.

He explained that by using low doses of drugs like 5-azacytidine and 5-aza-2'-deoxycytidine, it is possible to separate the killing effects of these drugs from the reprogramming effect, in which cancer cells are given a new "memory" to convert them to a less tumorigenic state.

"We will have a very exciting time over the next 3 years. We're learning to improve therapy for leukemia with these drugs by [changing] how we give them in terms of dose and timing; in addition, we are now gaining traction in solid tumors. There's a lot of excitement in patients with advanced lung cancer who have failed previous chemotherapy," he noted.

Dr. Baylin added that a subset of these patients — in early results from a trial being conducted by his colleagues at Johns Hopkins University, Charles Rudin, MD, and Ros Juergens, MD — are showing robust responses with stable or remission rates totaling up to 30%. "Some responses are lasting up to a year or more in a setting where one would usually only expect about 4 months after failing chemotherapy," Dr. Baylin announced.

These findings have led to the planning of intensive trials, under the aegis of the Stand Up to Cancer program, in a joint venture with the American Association for Cancer Research, which are scheduled to begin over the next 3 years in lung, colon, and breast cancer.

Robin Foa, MD, president of EHA and head of the Division of Hematology at Sapienza University in Rome, Italy, said that hematology is often a front-runner in innovative forms of management from diagnosis to prognosis and treatment.

"This research is a further step forward in the treatment of hematological malignancies. As hematologists, we are often a step ahead, and we've known this for many years. For example, in Philadelphia-positive acute lymphoblastic leukemia, the worst disease in hematology, if not in medicine, we can now put patients into remission even at 80 to 90 years of age without chemotherapy, just with a tyrosine kinase inhibitor."

Commenting on Dr. Baylin's work, Dr. Foa said: "What we have just heard is a further development that has stemmed from knowledge in the field of epigenetics, and it is likely that in the near future, whole genome sequencing will further change the management of patients with hematological malignancies."

Dr. Baylin, Dr. Rudin, and Dr. Juergens have disclosed no relevant financial relationships. Dr. Foa reports serving, on occasion, on the advisory boards of Roche, GSK, BMS, Celgene, and Biogen. The Stand Up to Cancer program trials are funded by the Entertainment Industry Foundation.

15th Congress of the European Hematology Association (EHA). Epigenetic Events: New Targets. Presented June 13, 2010.