VCU researchers identify new drug combination that could help patients with deadly blood cancer

By Lorraine Cichowski and Steven Grant

RICHMOND, Va. – Researchers at Virginia Commonwealth University’s Medical School and Massey Cancer Center have discovered that combining the novel drug, UCN-01, with an experimental drug that blocks activation of a collection of key proteins whose many functions include regulating cell death could present a new strategy for treating the incurable blood cancer, multiple myeloma.

In a study published in the April 1 issue of the journal Blood, VCU researchers report that exposing multiple myeloma cells to UCN-01 in combination with the experimental agent Bay 11-7082 markedly increased cell death, including some cells resistant to steroids – a common treatment for multiple myeloma, a type of cancer formed by malignant white blood cells in the bone marrow.

The findings suggest another possible use for UCN-01, which currently is undergoing extensive clinical trials in humans whose cancers have become resistant to conventional treatments and whose effectiveness has been shown to increase in laboratory tests when combined with other new drugs or chemotherapy. They also indicate a potential role for Bay 11-7082 and similar compounds in treatment of multiple myeloma and other hematologic malignancies. Bay 11-7082 currently is not being developed as a pharmaceutical for use in humans, although some similar agents are in development.

“Until recently, the mainstays of treatment for patients with multiple myeloma have been steroids and cytotoxic drugs and, for those patients who are eligible, bone marrow transplantation,” said Dr. Steven Grant, Shirley Carter and Sture Gordon Olsson Professor of Oncology at VCU and lead author of the study. “An improved understanding of the mechanisms underlying enhanced survival of myeloma cells has led us recently to the clinical development of some new drugs, including Velcade, which is undergoing clinical trials. Despite these advances, however, the search for additional new agents and effective strategies against myeloma remains a high priority.”

UCN-01 is a novel anti-cancer drug that has shown promising results in laboratory studies in slowing or preventing tumor cell growth in a variety of cancers and appears particularly effective in triggering apoptosis in blood cancer cells. UCN-01 is known as a checkpoint abrogator because it interferes with the cell cycle regulation of cancer cells, including cell division and the ability of cancer cells to repair themselves after injury. 

Bay 11-7082 inhibits the activity of a collection of proteins known as Nuclear Factor-kappaB (NF-kB), which is involved in control of a large number of normal cellular processes, such as immune and inflammatory responses, cell development and growth and apoptosis (cell death), as well as certain diseases, such as cancer, arthritis and chronic inflammation. NF-kB remains latent in a cell’s cytoplasm, unless it is activated by a signal from outside the cell – including an oxidant such as cigarette smoke or an immune response. NF-kB then rapidly enters the cell’s nucleus, where it activates gene expression, including genes involved in preventing cellular death.  It is thought that continuous NF-kB activity protects cancer cells from apoptosis and could stimulate their growth. As a result, some new anti-cancer therapies such as Bay 11-7082 target NF-kB as part of cancer therapy.

Grant and his colleagues at VCU exposed drug-sensitive and resistant multiple myeloma cells to Bay 11-7082 and UCN-01. Separately, the drugs had little toxic effect on the cells.  Together, the agents resulted in a more than 50 percent increase in cell death after 24 hours of drug exposure, and further increases in cell death occurred during the next 48 hours.  The study found that steroid-resistant cells were as sensitive to the drug combination as the other cells.

“The findings have potential implications for the rational design of novel regimens targeted against multiple myeloma and related disorders,” Grant says.  

Grant is internationally recognized for his work on novel drug combinations to treat blood cancers. Previous studies by Grant’s laboratory have found that combined treatment with UCN-01 and another experimental drug -- 17-AAG -- appears to dramatically slow proliferation of several types of leukemia cells and trigger cell death and that combination of UCN-01 with drugs that interrupt the MEK1/2 pathway resulted in increased leukemia and myeloma cell death.

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