Discovery Could Boost New Therapies for Myeloproliferative Neoplasms

By Jim Stallard,

Thursday, July 23, 2015

Illustration of normal blood cells (red discs) along with cancer cells (black spheres) floating through a blood vessel.

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.

You can feel that the momentum has shifted.
Ross Levine
Ross Levine hemotologist/oncologist

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.

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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.

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Renewed Enthusiasm

“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.”

This shows a new path to making JAK2 drugs.
Ross Levine
Ross Levine hemotologist/oncologist

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.”

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Reading the above article, new therapies for MPN's, how does this apply to those of us how are JAK2 negative? I have essential thrombocytopenia, was officially diagnosised in 2011 but have had signs since 2007. My highest platelet count has been 1.2 million. I have been on hydroxyurea for 3 years.

Rita, thank you for your comment. We consulted with Dr. Levine, who responded: "The new approach we are investigating is not ready for clinical trials, but the overall idea would be to offer new JAK2-targeted treatments to all MPN patients, regardless of JAK2 mutational status. Our work over many years has shown that the JAK2 pathway, and JAK2-targeting drugs, offer benefit to all MPN patients whether they are JAK2 positive or not. But we restrict new treatment approaches to clinical trials for patients who are not getting benefit from standard, effective therapies like hydroxyurea."

I am happy to see this progress, feeling another challenge in my life, when I was diagnosed with MPN, 10 years after surviving AML. It was a coincidental finding, my platelets increased to 675 then 835 but most recently 690. I was found to be JAK2 positive at that time. I was wondering if those two things are related (my history of leukemia and 10 years later ET?) I am hopeful I will survive this too. Thanks

Krin, thank you for reaching out. This is an interesting and important question, and one we would advising discussing with your doctor. There is a chance there is some relationship between the 2 diagnoses, but the long time between them and the fact that the AML was first (and not second) makes it less likely.

I was diagnosed with ET in 1994 and PV in 2005 and JAK2 positive. I have been on hydroxyurea for 24 years, as well as having treatment with Anagleride, Warfarin, Aspirin, Clopidogrel, Pegylated Interferon, Clexane and Busulfan.
I have had many thrombotic and haemorrhagic events. I am classed as high risk. My spleen was removed in 1992, as I had severe splenomegaly and ITP. If there are ever any clinical trials for this new medication, would I be excluded for being asplenic? I have tried for inclusion in other JAK2 inhibitor trials, but excluded due to being asplenic.

Tereena, thank you for reaching out. We passed your question on to Dr. Levine, and he responds: "Current JAK2 inhibitors use spleen size as a major endpoint for clinical trial studies, which precluded asplenic patients from being included in the trial. However, if patients have other disease complications, including symptoms, which are improved with JAK inhibitors it might be worth discussing JAK inhibitor treatment in the setting of splenectomy with an expert. For the new drugs, it is too early to say, but our hope is to develop therapies which help patients in different ways, including for patients who have had their spleen removed."

I recommend that all MPN patients have full mutational testing done. I think this is usually referred to as a leukemia panel. The mutations you have in addition to JAK2, CALR & MPL can help determine your risk of transformation and even which treatments may work best for you. I had the test done and have only the MPL 515k mutation. This should put me at lower risk.

It's good to see the development of second generation Jak inhibitors. I just hope it's not too late for many of us as Jakafi fails to be effective over time.

A very exiting discovery! hopefull this lead to a good treatment for jak2+ Pv and Et. Hydrea and interferon is out of date! How long does it take to produce this new jak2 inhibitor?

Paul, we sent your question to Dr. Levine, who responded, "The compound studied in this report, CHZ868, is not suitable for clinical development, but we are working to develop a similar drug for human trials as soon as possible. These studies provided the needed evidence to justify an accelerated effort." Thank you for your comment.

I am very excited to read about CHZ 868 having just come across it several weeks ago. Is there any estimate as to when this new inhibitor would be introduced into clinical trials? Thank you.

Spike, thank you for your question. The compound CHZ868 is actually not suitable for clinical development, but researchers are working to develop a similar drug for human trials as soon as possible.

I was diagnosed with Essential Thrombocytosis (ET) 11 years ago .
I am JAK2 negative and CALR Positive.
I am on Pegasus interferon injections currently .
My platelets are now in the 570 -590 range. What drug would be your best option.

Paul, thank you for reaching out. We recommend you consult with your treating physician on this type of question, as every individual patient's best treatment is detemined by a large number of factors.

If you would like to make an appointment for a consultation with a Memorial Sloan Kettering Physician, please call our Physician Referral Service at
800-525-2225 or go to­care/appointment. Thanks for your comment.

Discovered that I have PMF a year ago. Age 72 meant no stem cell transplant. Began procrit to get hemo up. Successfully keeping it between 9-10; other cells all low. Symptoms of extreme fatigue, breathlessness, sleepiness returned for 4 wks so starting jakavi tomorrow 15mg twice daily.
Question, is this the standard move?
My hemotoligist doc is playing catch up on the
disease. I have gotten my name on Dukes drug trial list, but so much to learn! Thank you. Oh I am jak2 negative.

Carolyn, thank you for reaching out. We recommend you consult with your treating physician on this type of question, as every individual patient's best treatment is detemined by a large number of factors.

If you would like to make an appointment for a consultation with a Memorial Sloan Kettering Physician, please call our Physician Referral Service at
800-525-2225 or go to­care/appointment. Thanks for your comment.

What about this new drug and myelofibrosis?

Lisa, thank you for reaching out. We consulted with Dr. Ross Levine on your question, and he responds:

CHZ868 is a preclinical, novel JAK2 inhibitor which showed significant activity in our model systems. This knowledge is being used to develop and test novel JAK inhibitors in the laboratory, which we hope will represent novel therapies for MF patients.

I just found out that my best friend's Mom is JAK2 positive. She lives in AZ. I live in the NY metro region. She is like a Mom to me and really lifted me up when I needed it. I believe she is in her early 70's it is hard to keep track of time. They say she can't have a transplant because there is too much scarring and she may not survive the treatment. I want to be able to help. I don't know if you offer better treatment options at MSK than what is available in Phoenix area for myelofibrosis? Is there any advise you can give me or people to contact that could offer such support or direction? I read that benzene or toluene can cause this mutation and she drank gasoline as a teen by mistake and was hospitalized could this stem from this incident or should her children be tested for JAK2? It seems the answer may not be clear cut? Is it? I know she tried Jakafi and her platelets went really low so she had to stop. She is bleeding and doesn't know why. I just wish I could help or support her in some way. Thank you for any response.

Dear DeeDee, we are sorry to hear about your best friend's mother's diagnosis. If she would like to make an appointment with one of our specialists to discuss her treatment options, please ask her to call our Physician Referral Service at 800-225-2225. We also offer genetic counseling and testing for genetic mutations (such as JAK2) associated with an increase in cancer risk. To learn more about our Clinical Genetics services and when testing is recommended, please visit… or call 646-888-4050. Thank you for reaching out to us.

Any new developments with CHZ868?

Chris, thank you for your question. The compound CHZ868 is actually not suitable for clinical development, but researchers are working to develop a similar drug for human trials. Unfortunately, it's still too early to estimate when such trials may begin.

Recently diagnosed with Myeloproliferative Disorder JAK2 Positive. I am confused and do not know who to follow up with and how to monitor this?? Any help would be great.

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