Thursday, July 23, 2015
Blood cancers called myeloproliferative neoplasms (MPNs) are driven by mutations in a gene called JAK2. Current drugs that inhibit the protein made by mutated JAK2 don’t work as well as initially hoped. A new compound that targets this protein when it is in an inactive structural state appears to be more effective and less toxic, raising hopes that this will lead to better drugs for MPNs.
- Myeloproliferative neoplasms (MPNs) are a group of blood cancers.
- MPNs are largely caused by mutations in a gene called JAK2.
- New compounds may work better than current drugs in treating MPNs.
- They target the JAK2 protein in a different structural state.
Memorial Sloan Kettering researchers are reporting what could be a significant advance in the treatment of blood cancers known as myeloproliferative neoplasms (MPNs). A new compound appears to be effective at blocking a protein, JAK2, that plays a key role in these diseases but has proved stubbornly resistant to current drugs.
The discovery, reported by hematologist/oncologist Ross Levine and colleagues, has energized a therapeutic field that had been foiled by MPN cancer cells’ ability to withstand drugs that seemingly hit their target.
“You can feel that the momentum has shifted, and the fact that we have had a major role in changing the momentum is gratifying,” Dr. Levine says.
The Two Faces of JAK2
MPNs are diseases in which the bone marrow produces several types of blood cells in excess. Earlier research by Dr. Levine and others found that cancer cells in many people with MPN have a mutation in the JAK2 gene or in other genes that interact with JAK2 as part of the JAK2 pathway, which regulates a number of basic cell functions. Mutations in the JAK2 pathway can interfere with this process and promote cancer cell growth.
Although the JAK2 protein was a promising target, clinical trials testing drugs that inhibit this protein by binding to it have not led to dramatic clinical responses. The drugs improve disease-related symptoms and reduce spleen size, and one drug — ruxolitinib — was approved by the FDA for MPN patients. But the JAK2 inhibitors failed to bring about the striking molecular responses seen with other targeted therapies — most notably imatinib (Gleevec®), which is very effective against another blood cancer called chronic myelogenous leukemia (CML).
In 2012, Dr. Levine’s lab discovered that MPN cancer cells are capable of using an alternate means of maintaining the function of mutated JAK2 even when the cells are exposed to JAK2 inhibitors. This explained why current drugs are relatively ineffective, and it also bolstered the theory that the cancer cells need JAK2 to stay alive.Back to top
A New Approach
Given JAK2’s ability to persist in the presence of such inhibitors, Dr. Levine’s team considered another line of attack. JAK2 is a type of protein called a kinase, and many kinases actually cycle between an active and an inactive structural state — what biologists call a “conformation.” Drugs effective against one conformation might not work in the other.
Conventional JAK2 inhibitors such as ruxolitinib target the kinase in its active conformation. Dr. Levine’s lab decided to see whether a drug that binds to JAK2 in the inactive state would work better. This strategy of targeting a different kinase conformation when drugs are ineffective has worked before, he explained.
“[MSK physician-scientist] Charles Sawyers showed that a second-generation drug, dasatinib, worked in CML patients who failed imatinib because dasatinib binds to the target differently,” Dr. Levine says. “So there’s precedent in leukemias that if you hit the target when it’s in a different structural state, you might get better results.”
Dr. Levine and his colleagues collaborated with scientists at Novartis to develop a compound called CHZ868, which inhibits JAK2 in the inactive state. When they tested CHZ868 in mouse models of MPN and in patient samples, the drugs proved to be more effective and less toxic than first-generation JAK2 inhibitors. The researchers reported their results in the journal Cancer Cell.Back to top
“This shows a new path to making JAK2 drugs that will offer better therapeutic options,” Dr. Levine says. “I think you’re going to see another wave of drug development against JAK2.”
Dr. Levine explains that the exact compound used in the experiment may not actually go into patients. Researchers are busy improving upon it, and the final drug will likely be a slightly different compound that will work even better. But the study was essential in proving the effectiveness of targeting JAK2’s inactive state — and it underscores once again the importance of keeping the focus on JAK2.
“You’re seeing a groundswell, and a renewed enthusiasm among researchers and in industry that this is going to work,” Dr. Levine says. “It’s been very rewarding to be involved in this field as it’s progressed over the past decade — beginning when the role of JAK2 in MPN was first identified, to seeing the first drugs get to our patients, to today when it’s looking like we’ve found a way to something much better.”Back to top