Mechanism identified that increases effectiveness of therapy against leukemia drug combination is five times more effective than individual drugs alone

Abstract

Researchers from the Children's Cancer Hospital at The University of Texas M. D. Anderson Cancer Center reported that two specific drugs combined appear to be five times more effective than either agent alone against leukemia in the prepublished online issue of BLOOD Jan. 30, 2009.

For the first time, the researchers showed that the novel proteasome inhibitor, NPI-0052, shares similar functions as the histone deacetylase (HDAC) inhibitor, vorinostat. These cross-over similarities between the two anti-cancer agents increased cell death in chronic lymphocytic leukemia five-fold in preclinical tests. For acute leukemia, the efficacy was even greater.

"Our previous research on cell lines showed us that NPI-0052 was stronger than other proteasome inhibitors in fighting leukemic cells," says Claudia Miller, first author of the paper and graduate student at M. D. Anderson through the University of Texas Graduate School of Biomedical Sciences at Houston. "We wanted to improve the clinical efficacy of NPI-0052, so we started combining it with other agents and found that it was most potent when combined with HDAC inhibitors."

Joya Chandra, Ph.D., associate professor of Pediatrics and senior author on the study, worked with Miller analyzing the cause of the drugs' synergy in primary leukemia cells from human samples.

"We knew the two agents worked better together, but we were very surprised to find that the proteasome inhibitor and the HDAC inhibitor acted alike," Chandra says. "That's one of the reasons these two agents are so potent against leukemia."

The traditional role of proteasomes is to clean out mutated or damaged proteins within cells, which promotes cell growth and allows cancer cells to rapidly reproduce. Proteasome inhibitors, such as NPI-0052, block this process, resulting in apoptosis, or cell death, of the malignant cells.

HDAC inhibitors work by allowing DNA strands within a cell to uncoil, which influences gene expression of that cell. The expression or repression of the cell's genes tips the balance in favor of the cancer cell to undergo cell death or to stop growing.

In the study, Chandra found that the two agents overlapped in function when the HDAC inhibitor repressed the proteasome from acting, and the proteasome inhibitor modified a protein that binds to DNA. This, in turn, enabled the cancer cell's DNA to uncoil, allowing for gene expression that promoted cell death.

"Combining the two anti-cancer agents should allow clinicians to use a lower dosage of each drug, which hopefully will result in fewer side effects for the patient," Chandra says. "For pediatric patients in particular, the fewer side effects they have from treatment could mean a better quality of life as survivors in the long run."

Chronic lymphocytic leukemia is the second most common form of leukemia in adults, and acute leukemia is the most common cancer in children.

NPI-0052 is currently being tested with solid tumor malignancies and recurrent lymphoma in Phase I human clinical trials at M. D. Anderson. A combination trial to test NPI-0052 with vorinostat is in the planning.

In addition to Chandra and Miller, other authors on the study are Sharmistha Rudra, Michael J. Keating, M.D., William Wierda, M.D., Ph.D., and Michael Palladino, Ph.D.

Funding for the study was provided through two National Institutes for Health grants, the Children's Leukemia Research Association, the Center for Cancer Epigenetics at M. D. Anderson and other philanthropic funds.