Histiocytic diseases are a group of blood disorders that affect both children and adults and can lead to severe disability and death. Until recently, there were no effective treatments for the more severe forms of these diseases in adults. However, it was recently discovered that about half of these patients have a mutation in a gene called BRAF and that treating these patients with a medicine that blocks this mutation results in astounding benefits for these patients. Unfortunately, half of histiocytosis patients do not have the BRAF mutation and therefore cannot benefit from this breakthrough therapy. We and others have conducted intensive genetic analyses of these “non-BRAF” patients and found that nearly all have mutations in other genes that turn on a single tumor growth pathway. Fortunately, a class of medicines (called “MEK” inhibitors) blocks this pathway and in compassionate use protocols we have provided this drug to 2 adult patients dying from a histiocytic disorder with dramatic resolution of grave symptoms.
Based on these data, we believe that MEK inhibition will provide an important new therapy for those patients without the BRAF mutation as well as an opportunity to understand the pathways that drive these disorders in more detail. In this grant we propose to test the effects of the MEK inhibitor, cobimetinib, in a clinical study in these non-BRAF patients and study the biological importance of the diverse non-BRAF mutations in histiocytic disorder patients.
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