Epigenetics and how it is producing new therapies for blood cancer patients
I have mentioned here before the field of epigenetics, a word meaning "above the genome" and referring to small chemical additions that alter critical gene activities without changing (mutating) the DNA code of those genes. The alterations include the addition of methyl or acetyl chemical groups to DNA and DNA-associated molecules (known as methylation, acetylation).
As usual, epigenetics was first discovered in so-called "model systems," fruit flies and mice where eye color and coat color can be determined by epigenetics as well as specific DNA sequences. There was recently a fascinating Nova episode describing some of this work.
Often epigenetics alterations inactivate ("silence") particular genes. So-called "tumor suppressor" genes normally make cells mature into various types of productive but non-proliferative cells and make damaged cells die, and cancers arise when these genes are inactivated. As with DNA mutations, specific epigenetic abnormalities can inactivate tumor suppressors to cause cancers to arise, survive and expand.
Epigenetic abnormalities include alterations in the methylation of DNA regions that control gene activity and acetylation on the histone proteins that bind DNA to fine-tune control. And, it seems that some of those micro RNAs that I have discussed can cause cancer by producing abnormal DNA methylation patterns.
Blood cancer research led to the first availability of drugs that can reverse epigenetic abnormalities. 5-azacytidine/VIDAZA® was approved by the U.S. Food and Drug Administration (FDA) as a treatment for patients with myelodysplastic syndrome (MDS) in 2004, and decitabine/DACOGEN® was FDA-approved for MDS patients and vorinostat/ ZOLINZA® was approved for patients with cutaneous T-cell lymphoma in 2006.
The first two drugs work by reducing DNA methylation, while ZOLINZA inhibits the removal of acetyl groups (deacetylation) to increase histone acetylation. In both cases, tumor suppressor genes get reactivated and cancer cells die. These targeted drugs are now being tested as treatments for a wide range of cancer patients, and patients with Alzheimer's, autism, and other serious illnesses, as highlighted in a recent Washington Post story that suggests we may someday also be able to control epigenetics to prevent cancer!
Researchers funded by The Leukemia & Lymphoma Society (LLS) accomplished many of the studies that led to epigenetic-targeting drug approvals, and they continue to make advances in this field. Guillermo Garcia-Manero, M.D., at M.D. Anderson Cancer Center helped show that DACOGEN could effectively treat MDS patients. He recently reviewed studies, including his own LLS-funded studies, showing that certain tumor suppressor genes are inactivated by epigenetics in cases of acute lymphocytic leukemia (ALL). Dr. Manero has shown that this information can be used to identify those ALL patients who are most likely to benefit from epigenetic-targeting treatments.
Ari Melnick, M.D., of Cornell Weill Medical College, has been developing new technologies that allow tens of thousands of different genes to be simultaneously interrogated for epigenetic as well as genetic abnormalities. He has applied these tests in breakthrough studies of the causes and treatment-sensitivity of leukemias and lymphomas. He is the senior author of a breakthrough report published in the prestigious scientific journal, Cancer Cell.
As in ALL, treatment plans for patients with acute myeloid leukemia (AML) are currently based largely on genetic features of individual cases, but patients with apparently identical genetics can respond very differently to today's anti-cancer therapies. Dr. Melnick's group measured methylation in 14,000 genes in samples from 344 AML patients and discovered sixteen distinct methylation patterns, five of which defined entirely new AML subtypes. Methylation levels on fifteen genes predicted patient survival better than standard tests. Forty five genes were almost always methylated in AMLs, making them far more common than any genetic abnormality and providing good leads for new targeted therapies.
Steven Grant, M.D., of Virginia Commonwealth University and Massey Cancer Center, has been a leader in developing histone deacethylase inhibitors for blood cancer patients. He recently led a Phase 1 clinical study in which ZOLINZA was combined with bortezomib/VELCADE® for relapsed/refractory myeloma patients. An optimal, safe dose of ZOLINZA was identified in this drug combination that produced an overall response rate of 42% in 23 patients. Larger trials are now warranted.
LLS grantees, Steven Gore, M.D., of Johns Hopkins University and Jonathan Licht, M.D., of Robert H. Lurie Comprehensive Cancer Center, participated in a study led by Dr. Melnick, mentioned above. This research group studied samples from MDS, AML and chronic myelomonocytic leukemia patients who participated in a Phase 1 clinical trial of a newer histone deacetylase inhibitor plus the methylation inhibitor, VIDAZA. They found that DNA methylation was reversed after the first treatment cycle and the reversal persisted in association with some clinical responses. A full report of clinical findings is expected soon, but their findings suggest that combinations of different epigenetics-targeting drugs may be particularly effective.