Drug Successfully Treats Chronic Blood Cancer In Mice

Armen Hareyan's picture

Researchers at Brigham and Women's Hospital have successfully treated a chronic blood cancer in mice using a novel designer drug to attack a mutant protein that triggers malignant blood cell growth. They say it shows promise as a definitive treatment for myeloproliferative diseases (MPD), which affect some 80,000 to 100,000 people in the United States.

The drug shut down or reduced abnormal production of blood cells in the bone marrow and spleens of mice with polycythemia vera, one of three MPD cancers, according to a report in the April 7 issue of Cancer Cell by a group led by Gary Gilliland, MD, PhD, at Brigham and Women's. He is also affiliated with Dana-Farber Cancer Institute and Harvard Medical School, and is an Investigator of the Howard Hughes Medical Institute.

The positive results in animal testing have already prompted the launching of phase I clinical trials in patients at Dana-Farber and other centers to study the safety in humans of trials of the drug, TG101348, which caused no toxicities in mice.

"A betting person would be excited about this," said Richard Stone, MD, an oncologist who is leading the clinical study at Dana-Farber.

Scientists at TargeGen Inc., a biopharmaceutical company in San Diego, designed the compound to selectively block a mutant protein growth signal, JAK2, that drives the majority of cases of polycythemia vera, essential thrombocytosis, and primary myelofibrosis.

There currently are few good treatments for the myeloproliferative diseases, and although patients may live with them for a number of years, they can cause serious complications and morph into a lethal form of leukemia.


In the mice, TG101348 decreased the amount of cancer and dramatically increased the survival rate. The first rationally designed targeted drug for a cancer, Gleevec, has vastly improved the outlook for patients with chronic myelogenous leukemia (CML), which is related to the MPD, and Stone and Gilliland said they are optimistic that TG101348 or a related drug might have a similar impact on the myeloproliferative disorders, which are five times as prevalent as CML.

Gilliland and colleagues at Brigham and Women's and Dana-Farber reported in Cancer Cell in 2005 that most cases of MPD are triggered by a mutation in the tyrosine kinase JAK2, an enzyme that promotes the growth of blood cells. The mutation in JAK2 is like a broken switch that leads to runaway growth of red and white blood cells. The team had used the Internet to request and obtain blood samples from patients with MPD, and used robots to sequence their DNA in the hunt for the mutation.

"In less than three years since the discovery of the mutation, we have worked in a collaboration between academia and industry to carry out preclinical development of the drug, and it is now in phase I trials," said Gilliland. "It is truly remarkable, given that drug development often takes a decade or longer."

The precise cause of MPD, as with many cancers, is unknown. Patient experiences differ widely, but the overproduction of blood cells and the damage to normal bone marrow cells can lead to painful spleen enlargement, clots, bleeding, and infections. Some patients eventually develop acute myelogenous leukemia (AML), which, especially in older patients, is often fatal.

Led by Gilliland and Gerlinde Wernig, MD, lead author of the Cancer Cell report, the researchers created a mouse model of polycythemia vera by transplanting bone marrow cells containing the mutant JAK2 enzyme into mice.

Mice were treated with TG101348, a small-molecule kinase inhibitor administered orally, or a placebo. All the animals in the treated group survived, whereas a significant proportion of mice in the placebo group died. Importantly, the drug had no effect on normal blood cell production or immune function.

The drug shrunk the enlarged spleens, reduced abnormal blood cell production and reversed myelofibrosis in some drug-treated animals - scarring of the bone marrow tissue in severe cases of MPD. In the early clinical trials, patients with myelofibrosis will be the first to receive the experimental drug, said Ann Mullally, a research fellow at Dana-Farber and co-investigator on the clinical trial there.

"Our overall plan," said Gilliland, "is to determine if the drug is safe and effective, and ultimately to determine if other types of cancers may be amenable to treatment with JAK2 inhibitors."