Cancer Drug Takes Fast Track to Clinical Trials
Small-molecule Kinase Inhibitor Shows Promise for Treating Family of Blood Disorders
In an industry that sees drug development frequently take more than a decade, it is a remarkable feat, indeed, when a drug target can be identified and taken to clinical trials in three short years. This is the case for a new cancer drug that has just entered phase I clinical trials following its striking efficacy in a mouse model of polycythemia vera (PV)—a blood cancer that causes unregulated growth and proliferation of red blood cells in the bone marrow.
The Need for Therapy
Although typically the diseases are relatively slow to develop, with patients living for many years exhibiting relatively mild symptoms, there are marked thrombotic and bleeding risks associated with MPDs. Sometimes they transform into more acute, lethal forms of leukemia. Currently patients are treated with empirically derived chemotherapy such as hydroxyurea and other agents that may be accompanied by significant side effects.
The first treatment breakthrough for MPDs occurred in the 1990s with the
identification of a mutant BCR–ABL fusion protein in patients with
chronic myelogenous leukemia (CML), a subgroup of MPDs that specifically
affects white blood cell production. A few years after its identification,
a small molecule inhibitor was designed against the mutant protein and found
to be highly effective in the treatment of CML, with the majority of patients
going into remission.
Near-100 Percent Prevalence
“This was a ground-breaking result because usually if you find a mutation in a disease entity, you’re happy if it has a frequency of 10 to 15 percent,” explained Gerlinde Wernig, first author on the Cancer Cell paper. “With this mutation, it turned out that over 95 percent of the entire population of patients with PV were positive for the JAK2 mutation.”
In normal individuals, JAK2 kinases are present on the plasma membrane of red blood cells and serve as an “on” switch for cell growth and proliferation. When turned on, they activate a signaling pathway that tells the cell to grow following the binding of the red cell growth hormone erythropoietin. In PV, however, the mutated form of the JAK2 protein behaves like a broken switch that is constantly in the “on” position, leading to unregulated growth and proliferation of red cells regardless of whether erythropoietin is present or not.
In 2006, Gilliland’s team reported success in developing an effective mouse model of PV through expression of the mutated JAK2 protein in recipient mice. In the two years since, the researchers have been collaborating with the pharmaceutical industry to identify candidate drugs—specifically targeting the mutant JAK2 protein—that would attenuate the signs and symptoms of PV in their mouse model.
“We thought it was important to establish fulminant disease prior to initiation of therapy, so that we were able to assess whether a drug can treat the disease into remission, rather than simply preventing its development,” explained Gilliland.
Following several failed attempts with drugs that were either ineffectual or poorly tolerated, the team finally hit the jackpot with a small-molecule JAK2 inhibitor developed by a San Diego-based company, TargeGen Inc. After dosing mice with either the JAK2 mutant inhibitor or placebo twice daily for seven weeks, the team assessed measures such as survival and blood cell count. They also looked at other measures that might be useful as markers for predicting long-term outcomes in patients.
The JAK2 mutant inhibitor is now undergoing phase I clinical trials at the Dana–Farber Cancer Institute, led by associate professor of medicine Richard Stone and clinical fellow in medicine Ann Mullally, with the aim of determining the safety of the drug in humans.
“Drug development in the modern era can proceed very rapidly,” said Gilliland. “We are now positioned in cancer biology to make significant inroads as we identify and validate targets and animal model systems and begin to translate those findings into humans. It speaks to the motivation both of academic efforts and industry efforts, to move drug development for cancer along at a more rapid pace.”