Combination of velcade anti-cancer drug and second novel agent shows promise for leukemia patients

By Lorraine Cichowski and Steven Grant

RICHMOND, Va. – Combining the cutting-edge drug Velcade (bortezomib) with a second novel agent that appears to stop the growth of cancer cells by blocking key enzymes effectively killed leukemia cells, including those that had become resistant to other chemotherapy drugs, according to a new study by researchers at Virginia Commonwealth University.

The findings, reported in the Nov. 15 issue of the journal Blood, suggest a new use for Velcade and raise the possibility that a combination of Velcade and experimental drugs known as histone deacetylase inhibitors may be useful for treating patients suffering from chronic myelogenous leukemia, a malignant cancer of the bone marrow and one of the most-common forms of leukemia.  The study was published early online.

“We found that this combination was quite lethal to chronic myelogenous leukemia cells, which are generally resistant to standard chemotherapy agents,” says Dr. Steven Grant, Shirley Carter and Sture Gordon Olsson Professor of Oncology at VCU and lead author of the study. “On its own, Velcade has not been shown to be an effective treatment option for this form of leukemia. However, Velcade and histone deacetylase inhibitors appear to interact synergistically to induce cell death in chronic myelogenous leukemia, at least in the test tube, thus representing a novel treatment approach.” 

Velcade is the trade name for bortezomib, the first of a new class of anti-cancer medicines known as proteasome inhibitors, which induce cancer cell death by altering the abundance of key proteins involved in cancer cell proliferation and survival. Proteasomes are enzyme complexes that exist in all cells and regulate levels of these proteins by controlling their degradation. Inhibiting proteasome activity appears to cause apoptosis, or programmed cell death, in cancer cells but has little impact on normal cells.

Velcade, which is administered by injection and is distributed by Millennium Pharmaceuticals, Inc., of Cambridge, Mass., was approved by the Food and Drug Administration in May under an accelerated approval program for treatment of multiple myeloma, which is a type of cancer formed by malignant plasma cells -- white blood cells in the bone marrow. Velcade was the first new treatment in more than a decade to be approved for patients with multiple myeloma. It is recommended for patients whose disease has relapsed twice after two prior treatments and who have demonstrated drug resistance after their last treatment.  It is undergoing clinical trials for treatment for a wide variety of blood and solid tumor cancers, including leukemia, lymphoma, prostate, colon and lung cancer. 

The histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), also is in clinical trials as a cancer therapy. Histone deacetylase inhibitors appear to work by modulating signal transduction pathways in cells, disrupting the cell cycle in a way that slows proliferation of cancer cells and encourages their death. Histone deacetylase inhibitors also activate genes involved in cell differentiation and many other cellular functions.

Grant and a team from VCU that included researchers in medicine, radiation oncology, biochemistry, microbiology, human genetics and pharmacology, treated chronic myelogenous cells with different combinations of Velcade and two types of histone deacetylase inhibitors -- sodium butyrate and the newer, second-generation inhibitor SAHA. They found that treatment of the cancer cells with Velcade, SAHA or sodium butyrate alone were minimally toxic to the cells.  However, treating the cells with combinations of Velcade and one of the histone deacetylase inhibitors resulted in a very marked increase in cancer cell death.

Significantly, the combination also proved to be effective in cancer cells that had become resistant to Gleevac, an oral anti-cancer drug sold in the United States by Novartis Pharmaceuticals Corp. that has become a common and very effective treatment option for patients with chronic myelogenous leukemia. The development of drug resistance represents a major barrier to cure of chronic myelogenous leukemia as well as most other neoplastic diseases.

“Although this work is at a relatively early stage, our initial laboratory results are encouraging,” said Grant, who hopes to develop clinical trials based upon these findings within the next 1-2 years at VCU’s Massey Cancer Center. 

Grant is internationally recognized for his work on novel drug combinations to treat blood cancers. He currently is leading a multi-center, Phase I, clinical trial sponsored by the National Cancer Institute to test a combination of Gleevac and Flavopiridol, made by Aventis, for treating chronic myelogenous leukemia and related leukemias. 

The American Cancer Society estimates that 30,600 new cases of leukemia will be diagnosed in the United States in 2003, and 21,900 adults and children will die of the disease.

The study was supported by grants from the National Cancer Institute and the Leukemia and Lymphoma Society of America.