One of the great challenges in oncology is development of rational therapeutic regimens, truly specific to pathogenic mechanisms. Achieving this in the context of acute myeloid leukemia (AML), a generally fatal tumor with extremely heterogeneous underlying biology, is both an urgent and challenging unmet need. Yet an AML subtype, acute promyelocytic leukemia, was the first tumor to be rendered curable by mechanism-based therapy.  In this case, convergence of therapy and biological mechanism emerged in a somewhat serendipitous manner.  However, it is of paramount importance to extend this novel therapeutic paradigm to a greater fraction of leukemia patients through rigorous translational research.  

More recently, exploring the epigenome of patients with AML led to another serendipitous convergence with potential to transform clinical practice.  Specifically, a subset of AML patients with somatic mutations in the genes IDH1, IDH2, TET2 and WT1 were observed to manifest a highly distinctive epigenetic profile.  Although previously these genes had been considered functionally disconnected, different lines of research were providing clues that fit together to reveal a completely novel pathogenic mechanism.  Central to this new paradigm was the discovery that mutant forms of IDH produce the aberrant onco-metabolite 2HG, which disrupts the function of epigenetic modifier enzymes and transcription factors.

The flurry of activity stemming from this new mechanistic discovery led to the rapid development of targeted small molecules with specific activity against mutant forms of the IDH1 and IDH2 enzymes, which led to rapid translation into the clinic where these agents are now clinically available for patients with AML harboring IDH1 or IDH2 mutations.  This year’s Ernest Beutler Award recipients will present this inspiring bench-to-bedside development story.

Dr. Ari Melnick will describe how defining the “epigenetic landscape” of hematologic malignancies led to demonstration of the role of epigenetic mutations as cancer drivers, highlighting how epigenetic targeted therapies can restore normal transcriptional programming in leukemic cells leading to their eventual extinction.   

Dr. Courtney DiNardo will summarize the recent advances in the clinical care of patients with AML, including small molecule and targeted “epigenetically-active” therapeutics such as the targeted and rationally designed IDH inhibitors that are rapidly changing the treatment landscape and overall expectations of AML therapy.