Temple Researchers Show Promising Results with New Epigenetic Drug for Leukemia, Myelodysplastic Syndromes

Promising results from an early stage, multicenter clinical trial led by researchers at Temple University School of Medicine have shown that a novel drug that alters the behavior of cancer cells may help patients with leukemia, as well as those with potentially dangerous blood disorders that frequently lead to leukemia. The findings, while preliminary, could lead to a new approach to treat various forms of cancer using a type of drug called a methylation inhibitor that seeks to modify changes to DNA that lead to cancer.

“It’s a new and better drug that targets DNA methylation, the biochemical modifications that essentially serve as bookmarks for when a gene will be turned on or off, and which often play important roles in cancer development,” said Jean-Pierre Issa, MD, Professor of Medicine and Director of the Fels Institute for Cancer and Molecular Biology at Temple University School of Medicine in Philadelphia, who led the work. Dr. Issa presented his team’s results Sunday, April 1, 2012, at the American Association for Cancer Research (AACR) Annual Meeting 2012 in Chicago. AACR is the scientific partner of Stand Up To Cancer, which supported the research.

Cells frequently use chemical tags called methyl groups to mark certain genes, indicating whether their instructions should or should not be followed for making proteins, but this system often goes awry, leading to cancer. Gene methylation is an example of epigenetics, which are modifications – sometimes inherited, often environmentally caused – to chromosomes and genes other than changes in the DNA sequence itself.

Dr. Issa calls methylation “the instruction manual of the cell,” providing guidance for how the body uses DNA. In cancer, this manual can malfunction, he said, and the methylation tags redistribute themselves, in turn, mistakenly activating or deactivating certain genes, potentially leading to cancer or other diseases. Where chemotherapy attempts to kill cancer cells, epigenetic drugs such as DNA methylation inhibitors try to make such wayward tags – and cancer cells – normal again, in essence, rewriting the instruction manual. According to Dr. Issa, many current methylation-inhibiting drugs have limited use, particularly because they often cannot sufficiently get inside cells.

In the study, Issa and colleagues examined the use of a novel DNA methylation inhibitor, SGI-110, which they developed along with Astex Pharmaceuticals. SGI-110 is an alternate form of an existing epigenetic drug, decitabine, which quickly degrades in the body, limiting its effectiveness. The researchers hoped SGI-110 would last longer, and be more effective.

In a first-in-human phase I clinical trial, researchers randomly assigned patients with relapsed or refractory intermediate- or high-risk myelodysplastic syndrome or acute myeloid leukemia to one of two different dosing schedules of SGI-110 in order to establish a biologically effective drug dose and to also see how the drug was tolerated. Acute myeloid leukemia (AML) can be a fast moving and deadly form of blood cancer. Myelodysplastic syndromes (MDS) include several different types of potentially very dangerous blood disorders, some of which may lead to leukemia.

To date, 66 patients have been enrolled in the trial, and at least three patients have had disease remission, with two complete responses and one partial response. The drug has shown a longer half-life, and has been well tolerated, with side effects including anemia.

“These patients have few options left, and these results are encouraging. We hope SGI-110 will be a better drug than what we currently have, and we can deliver more of it more efficiently to cancer cells,” Dr. Issa said. He noted that his team will to continue to study SGI-110 in a phase II trial, and is planning to examine the use of the drug in other types of common cancers, including lung and breast cancers.

In addition to Issa and Woonbok Chung from Temple University, other researchers involved in the study include Gail Roboz, Weill Cornell Medical College; David Rizzieri, Duke University Medical Center; Stefan Faderi and Hagop Kantarjian, M.D. Anderson Cancer Center; Casey O’Connell, USC Keck School of Medicine, University of Southern California; Wendy Stock, University of Chicago Medical Center; Raoul Tibes, Mayo Clinic Arizona; Elizabeth Griffiths, Roswell Park Cancer Institute; Karen Yee, Princess Margaret Hospital; Gavin Choy, Aram Oganesian, Pietro Taverna and Mohammad Azab, Astex Pharmaceuticals.