Somatic Genetic Alterations in the Pathogenesis and Therapy of Histiocytic  Disorders

Julien Haroche, MD

Omar Abdel-Wahab, MD (Memorial Sloan Kettering Cancer Center, New York, NY US)

In September 2013, the ECD Global Alliance announced a $50,000 2013 ECD grant was awarded to Omar Abdel-Wahab, MD, David Hyman, MD, and Eli Diamond, MD from Memorial Sloan-Kettering Cancer Center in New York (MSKCC), New York for the study described as, “Somatic Genetic Alterations in the Pathogensis and Therapy of Histicytic Disorders”.  As described in the MSKCC press release, the aim of this study is to:

  1. Identify recurrent somatic genetic events in addition to BRAFV600E mutations in patients with ECD.
  2. Identify cell of origin in ECD.
  3. Identify the optimal targeted therapy in histiocytic disorder patients with mutations activating kinase signaling.

This project was completed in February 2015.  The team at MSKCC supported a phase II study of vemurafenib in ECD and LCH patients bearing the BRAFV600E mutation, performed a study in collaboration with Filip Janku, MD, PhD at MD Anderson Cancer Center to understand how blood and urine could be used to track the BRAFV600E mutation in ECD patients undergoing therapy, collaborated with Drs. Julien Haroche and Jean-Francois Emile in France to perform a large genomic study of ECD patients, and continues to perform and even larger genomics study in ECD.  Multiple journal articles were published in part as a result of this project.

Amount:  50,000 USD

Final Report

  • The phase II study of Vemurafenib in ECD and LCH patients bearing the BRAFV600E mutation was completed. This study was carried out in the context of an international study sponsored by Roche and the results were submitted to the New England Journal of Medicine with Dr. Hyman as the lead author. The results of this study will result in FDA approval of vemurafenib for ECD and LCH patients with the BRAFV600E mutation in the U.S.
  • In addition, a phase II clinical trial of the MEK inhibitor cobimetinib for ECD patients without the BRAFV600E mutation was opened. This trial is sponsored by Genentech and is open for patient enrollment as of Spring 2015.

As a corollary to the vemurafenib clinical trial, a collaborative study was performed with Dr. Filip Janku at MD Anderson Cancer Center to understand the utility of cell-free

  • DNA analysis to identify and track the BRAFV600E mutation in ECD patients. This work revealed that plasma and urinary cell-free DNA-based detection of the BRAFV600E mutation is more sensitive than conventional tissue-based BRAFV600E mutation testing.
  • These findings were recently published in Cancer Discovery and featured as the cover article.

As a collaborative effort with Drs. Julien Haroche and Jean-Francois Emile the largest genomic study of ECD patients to date was completed, identified the true frequency of the BRAFV600E mutation in ECD as well as several, additional, novel therapeutically targetable mutations in ECD patients (including NRAS, KRAS, and PIK3CA mutations). This work was published in Blood and featured on the cover of Blood and in an “Inside Blood” Editorial.