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 story behind the discovery of this drug began three years ago with the identification of a molecular target—a mutant of the kinase protein JAK2—by Gary Gilliland, Howard Hughes investigator and HMS professor of medicine at Brigham and Women’s Hospital, and his colleagues. After finding the mutant, the team not only developed a mouse model of PV but, through collaborations with the pharmaceutical industry, was able to explore the effects of several candidate drugs that specifically target the mutant JAK2 kinase. In the April issue of Cancer Cell, Gilliland and his team report the effectiveness of one particular candidate drug that appears to revert a mouse model of PV into remission—apparently without any significant side effects.
The Need for TherapyPV is one of a heterogeneous group of blood cancers known as myeloproliferative disorders (MPDs). They occur in the bone marrow, causing proliferation of one or more blood cell lines, leading to an overabundance of a specific blood cell type. The different disease entities are classified according to the predominant cell type that they target; in the case of PV, red blood cell production is affected.
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.
While this new drug, imatinib (Gleevec), revolutionized therapy for CML, it was not effective for other MPDs, including PV, which are about five times more prevalent than CML. So the search continued for another molecular abnormality that might account for these other pathologies.
Three years ago, Gilliland’s group, among others, identified the mutant protein that seemed to account for a large proportion of the other MPD cases. The mutant turned out to be an abnormal variant of a naturally occurring kinase, JAK2, and appeared to be particularly prevalent in PV patients.
“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.
On face value, the initial obvious effect was that survival in the drug-treated mice was significantly higher than in the placebo group. The drug-treated group also showed a reduction in expression of JAK2 mutations at the end of the treatment period, suggesting that the disease had gone into remission. Another marker the group looked at was the strength of JAK2 signaling at the end of treatment and found that it, too, was significantly reduced, indicating that the drug was helping to calm down unregulated JAK2 activity. Furthermore, red cells from the drug-treated animals no longer showed the PV-specific phenomenon of being able to grow and proliferate in the absence of erythropoietin. The disease appeared to have gone into remission with no apparent effects on immune function.
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.”
