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New Treatment for a Deadly Childhood Disease

April 19, 2012

(Ivanhoe Newswire) — According to a recent study, two related enzymes, phosphoinositide-3 kinase (PI3k) gamma and delta, have been found to have a role in the development of an aggressive childhood leukemia (T-cell acute lymphoblastic leukemia (T-ALL)) that is highly difficult to treat.

The study sets the stage for clinical trials by revealing that a dual PI3K gamma/delta inhibitor can prolong survival in a mouse model of the disease and the dual inhibitor can prevent proliferation and reduce survival rate of human T-ALL cells in laboratory cultures.

“Clearly, we have a drug that is extremely effective against this type of cancer in mice.  If this treatment strategy can safely and selectively target the activity of these enzymes in T-ALL tumors, we might be able to reduce the need for conventional chemotherapies that more broadly affect proliferating cells, including those in healthy tissues. This would be a major advancement in helping to reduce drug toxicities in young patients,” study author, Thomas Diacovo, M.D., associate professor of pediatrics and pathology and cell biology at CUMC, was quoted as saying.

T-ALL is a type of cancer that comes during the development of T-cells.  The abnormal T-cells multiply and eventually invade and impair the functions of organs that are critical for staying alive.  Usually T-ALL develops during childhood, but can appear later in life.  T-ALL, if left untreated, can be lethal. The disease is caused by mutations in the DNA and is highly resistant to chemotherapy, causing the relapse rate to be 25 percent in children and 50 percent in adults.

Researchers used a mouse model of the disease in the first part of the study to confirm that both PI3K gamma and delta are essential for the T-ALL development and the survival of abnormal cells.  Also the researchers proved that administration of CAL-130 significantly lowers the number of leukemic T-cells in animals’ general circulation.

“The level of circulating leukemia cells dropped very rapidly, from an average of 100 million per ml to less than 1 million per ml within 24 to 48 hours.  The counts remained low after just 7 days of therapy,” Dr. Diacovo was quoted as saying.  The average survival rate for mice treated with CAL-130 was 45 days, compared to 7.5 days for untreated controls.

The effects of CAL-130 on blood samples taken from patients with T-ALL were also evaluated in the study.  The drug prevented proliferation of leukemic cells and promoted a self-destruct mechanism called apoptosis.

“We’ve made great strides in treating childhood acute lymphoblastic leukemia over the years, with an overall cure rate approaching 90 percent.  Unfortunately, this is not the case for T-All. In addition, conventional treatment– chemotherapy – is quite toxic. This is a particular problem for children, who have an entire lifetime ahead of them and are likely to develop secondary cancers and other complications as a result of their treatment. So anything we can do to lessen associated toxicities would be a welcome advancement in the field,” Dr. Diacovo was quoted as saying.

“Even in difficult-to-treat cancers–such as this form of childhood leukemia–our researchers are continually searching for less toxic ways to treat our patients, in an effort to improve their quality of life and to enable them to lead long, healthy lives. This is one of the key approaches to the future of cancer care,” Stephen G. Emerson, M.D., Ph.D., director of the Herbert Irving Comprehensive Cancer Center at New York-Presbyterian Hospital/Columbia University Medical Center, was quoted as saying.

SOURCE:  Cancer Cell, April 2012