Dysregulation of the histone methyltransferase EZH2 plays a critical role in the development of a variety of malignancies including B-cell lymphomas. As a result, a series of small molecule inhibitors of EZH2 have been developed and studied in the pre-clinical setting. Three EZH2 inhibitors: tazemetostat (EPZ-6438), GSK2816126 and CPI-1205 have moved into phase I/phase II clinical trials in patients with non-Hodgkin lymphoma and genetically defined solid tumors. Early data from the tazemetostat trials indicate an acceptable safety profile and early signs of activity in diffuse large B-cell lymphoma and follicular lymphoma, including patients with EZH2 wild-type and mutant tumors. In this review, we present the rationale, key pre-clinical and early clinical findings of small molecule EZH2 inhibitors for use in lymphoma as well as future challenges and potential opportunities for combination therapies.
Children with Langerhnans cell histiocytosis (LCH) develop granulomatous lesions with characteristic clonal CD207+ dendritic cells that can arise as single lesions or life-threatening disseminated disease. Despite the wide range of clinical presentations, LCH lesions are histologically indistinguishable based on severity of disease, and uncertain classification as an immune versus neoplastic disorder has historically challenged the development of optimal clinical strategies for patients with LCH. Recently, activating somatic mutations in MAPK pathway genes, most notably BRAFV600E, have been discovered in almost all cases of LCH. Further, the stage of myeloid differentiation in which the mutation arises defines the extent of disease and risk of developing LCH-associated neurodegeneration. MAPK activation in LCH precursor cells drives myeloid differentiation, inhibits migration, and inhibits apoptosis, resulting in accumulation of resilient pathologic dendritic cells that recruit and activate T cells. Recurrent somatic mutations in MAPK pathway genes have also been identified in related histiocytic disorders: juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease. New insights into pathogenesis support reclassification of these conditions as a myeloid neoplastic disorders. Continued research will uncover opportunities to identify novel targets and inform personalized therapeutic strategies based on cell of origin, somatic mutation, inherited risk factors, and residual disease.
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