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Emerging Role of MDM2 in Myelofibrosis Care

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Published on September 18, 2019

What is MDM2 and what does it mean for myeloproliferative neoplasm (MPN) patients? Leading expert Dr. Srdan Verstovsek, from The University of Texas MD Anderson Cancer Center, joined Patient Power to discuss this novel treatment option currently under clinical investigation for myelofibrosis (MF). Here, Dr. Verstovsek explains the mechanism of action of the MDM2 inhibitor and which patient population it may benefit. Watch now to find out more about myelofibrosis MDM2 treatment.

See below for a map of clinical trial sites.

This program is sponsored by Kartos Therapeutics, Inc. This organization has no editorial control. It is produced solely by Patient Power.


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Transcript | Emerging Role of MDM2 in Myelofibrosis Care

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

Andrew Schorr:

Dr. Verstovsek, so many of us with myelofibrosis, like me, have become familiar with the JAK2, maybe V617F gene and know that that could be active for us, and some of us have been taking a drug called ruxolitinib or Jakafi.  But I understand now you're looking into in a clinical trial something else called MDM2.  What is MDM2? 

Dr. Verstovsek:

So MDM2 is a protein that binds in the cells, in any cell, to another protein called the p53.  This is the very important protein in general, and particularly in cancer.  This is so‑called tumor suppressor and transcription factor.  In other words, p53 is involved in the regulation of what the cell does and the survival of the cell. 

When we have a normal situation in the human body and the cell is under stress, p53 is activated and leads to cell death.  That would then mean that in a cancerous cell there is lots of stress to the cell. It's not normal.  It's uncontrolled growth.  There should be death to that cell because of the activation of p53. However, it doesn't happen because there are inhibitors of p53 functioning in the cancer cell. 

One of those inhibitors is called MDM2.  So it's an inhibitor of p53 function.  It's a little bit of biology here that we are talking about that is important for the survival of the cell itself.  So cancerous cells, instead of dying, they are surviving because one of the major regulators of their survival and that p53 protein is inhibited.  And one of them is called MDM2. 

And here we are talking about a clinical study where we have an opportunity to provide patients with inhibitor of MDM2 protein.  So it's inhibitor of the  inhibitor of the p53 function allowing cells to die off.  That would be the ultimate, allowing cells, cancerous cells to die off and normal cells to flourish again and become—the bone marrow to become normal in myelofibrosis patients. 

Andrew Schorr:

Great.  So as I mentioned about the JAK inhibitors, how would this about different, and would it be beneficial to people maybe where a JAK inhibitor isn't working or no longer works? 

Dr. Verstovsek:

The underlying problem in myelofibrosis and other MPNs is hyperactivity of so‑called JAK/STAT pathway. This is a Cascade of proteins inside the cells that leads to uncontrolled cell growth.  We know why that happens because of mutations in the JAK2 gene or calreticulinor MPL gene, but the inhibition of the JAK/STAT pathway with the JAK inhibitors like ruxolitinib, although it can lead to a good control of the signs and symptoms of the disease for a very long period of time, for years, it does not have a potential to eliminate disease, resistance does develop, new mutations in the bone marrow still develop, and remember, that's a living tissue. 

So it continues to grow. Acquisition of new mutations happen. There are different parameters that we can measure and determine why patients fail, but that does happen, and in that situation we need to do something else for the patient. Situation is not easy after failing a JAK inhibitor.  You still have or you have again a big spleen, or you don't feel well, you lose weight, you have systemic symptoms, you may have anemia or low platelets, so it is not a very easy situation for the patient and for the doctor that cares about that particular person. 

So to change the spectrum of our ability to tackle the disease we are now moving on to other factors, not just the JAK/STAT pathway, other factors that are abnormal in cancer cells. Another factor is the activity of p53. That should lead to cell death, but it's not leading to cell death because it's inhibited, and MDM2 is one protein that inhibits the p53 function. 

So preventing the interaction between MDM2 and p53 is the goal of the MDM2 inhibitor.  This is where the new biology and our ability to develop new targeted agents for abnormal cancer cells comes to fruition.  It's not specific for myelofibrosis, but we know that MDM2 is highly expressed in baby cells in myelofibrosis, so‑called CD34 cells. So that would indicate that MDM2 has a huge importance for survival of malignant cells in myelofibrosis patients and makes sense to do a clinical study with the MDM2 inhibitor in patients with myelofibrosis, particularly in a second line after JAK inhibitors because of multiple other mutations, resistance to JAK inhibitors and other factors. 

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

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