Benjamin H. Durham, MD (Memorial Sloan Kettering Cancer Center, New York, NY US)
Memorial Sloan-Kettering Cancer Center in New York received a $50,000 research grant. Principal investigator, Benjamin H. Durham, MD, leads the study Defining the Cell-of-Origin of Erdheim-Chester Disease. The bone marrow cells from ECD patients will be studied to try to determine the cells that cause ECD. With this information, it may be possible to create a successful model of ECD that can be used for future studies by scientists from around the world. A secondary goal of this study will be to compare the gene profile of ECD cells with the cells of other blood cancers that are often seen in ECD patients. Dr. Durham is a hematopathologist and molecular genetic pathologist who has previously identified various genetic mutations associated with ECD. These findings have led to immediate therapeutic options for patients.
Amount: 50,000 USD
Final Report
Through comprehensive genomic sequencing analyses of the largest group of children and adults (270 patients) sequenced to date with histiocytic neoplasms of which the largest subgroup is Erdheim-Chester disease (ECD), several new and targetable kinase genetic alterations have now been discovered in ECD and other histiocytoses. The discovery of BRAFV600Emutations in these diseases around 8 years ago resulted in our understanding of these disorders as a type of cancer with future studies leading to the FDA-approval of vemurafenib for adult patients with BRAFV600E-mutated ECD (Hyman, D et al. NEJM 2015). However, it is still not clear what cell types lead to the development of ECD and other histiocytoses (Mass E, et al. Nature 2017) nor are all the genetic alterations in this disease defined. Here we identify the first examples of recurrent CSF1Rkinase mutations in any disease, as well as numerous additional new kinase alterations driving ECD and other histiocytoses.
The discovery of CSF1R mutations is significant because (1) CSF1R defines the monocyte/macrophage lineage and, therefore, reveals histiocytic neoplasms as derived from monocytes/macrophages, and (2) there are numerous inhibitors of CSF1R in development (and one is already FDA-approved for other diseases). We also demonstrate the first example of clinical responses to RET inhibition in RET-rearranged histiocytosis as well as evidence of preclinical responses to CSF1R inhibition in CSF1R-mutant cells. These data are highly clinically important and will be of immediate interest due to the excitement about CSF1R inhibition in cancer, RET inhibition, and precision medicine for rare disorders such as ECD.