Drs. Ari Melnick and Courtney DiNardo Awarded 2020 Ernest Beutler Lecture and Prize

The Ernest Beutler Lecture and Prize is being awarded this year to Ari Melnick, MD, of Weill Cornell Medicine in New York, and Courtney DiNardo, MD, of the University of Texas MD Anderson Cancer Center. The honor is named after the late Dr. Ernest Beutler, a past ASH president and physician-scientist with a remarkable career that spanned 50 years.

Dr. Melnick, who is receiving the Beutler award for basic science, explained that his personal approach to biomedical science involves committing 100 percent of his efforts to thinking deeply about disease mechanisms, and then working hard to find the root of the problem that needs addressing. “Hence, I am very honored and humbled to receive this award since I appreciate that it means my peers believe that I am meeting these standards… leading to significant advances in our field,” he commented. Dr. Melnick is a Gebroe Family Professor of Hematology/Oncology, professor of medicine, and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. His studies have shown that epigenetic mutations can serve as disease driver mechanisms and that epigenetic heterogeneity and clonality can influence the clinical outcome of these diseases. His career focuses predominantly on epigenetic mechanisms involved in the pathogenesis of hematologic malignancies. He spent years developing the first rationally designed transcription factor inhibitor for cancer treatment and the notion that the epigenome can serve as a “blueprint” containing instructions that provide tumors with their unique phenotypes. Interpreting this blueprint shows how leukemia and lymphoma cells work, which mechanisms induce abnormal instructions, and how to then target these cells therapeutically.

“In layman’s terms, you can think of the genome and the epigenome as the equivalent of the cell’s computer hardware and software, respectively. Just like a computer cannot carry out any functions without software, the same holds for the genome,” explained Dr. Melnick. He added to the analogy, “…software can be erased from computers and you can load new software and thus give it new or different functions. Again, the same is true for our cells.” While scientific advances aren’t there yet, Dr. Melnick believes we will eventually be able to erase and rewrite these instructions using therapeutic drugs. “We are therefore ‘hackers’ trying to read and change the software of leukemia and lymphoma cells to understand and then fix them,” he said. He also recognized another challenge in being able to find aberrant environmental niches in patients before they are seriously ill and to use that knowledge to resolve tumor progression early on.

Dr. Melnick has also observed that somatic mutations of genes encoding the enzymes IDH1 and IDH2 in acute myeloid leukemia (AML) are linked to specific DNA hypermethylation, and discovered a new cancer paradigm whereby founder mutations in diffuse large B-cell and follicular lymphomas cause aberrant persistence of cancer hallmarks that occur normally in germinal center B cells.

Dr. Melnick was drawn to hematology as a medical student because he saw it as the most advanced medical specialty in terms of understanding disease biology. He had great mentors along the way, including Dr. Jonathan Licht who shaped his understanding of science, adherence to professional ethics, and dedication to creative research. Looking back on his career in hematology Dr. Melnick expressed, “It’s a terrific field. As the hematologist, you are confronted by all kinds of amazing challenges and it is a truly bench to bedside field … it is very satisfying to be able to treat patients with therapies that are actually specifically created to solve the molecular basis of their disease rather than operate as toxic compounds in an indiscriminate manner.”

Dr. DiNardo, a clinical researcher in the Department of Leukemia, Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center, is being recognized for her translational/clinical achievements. Dr. DiNardo focuses on individualized therapy and precision oncology for AML, including the optimal incorporation of genomics into standard risk assessments and treatment algorithms, investigation for inherited hematologic malignancy syndromes, and the clinical evaluation of targeted therapies for molecularly defined patient subgroups. Her fellowship project on IDH1 and IDH2 mutations in AML helped define the relationship and significance of the unique 2HG oncometabolite, which occurs specifically in the setting of IDH mutations. As a result, she was involved early in the development of the small-molecule targeted IDH inhibitors, ultimately leading to U.S. Food and Drug Administration (FDA) approval of the first-in-class IDH2 inhibitor enasidenib and the IDH1 inhibitor ivosidenib. She believes, however, that the effective treatment of older patients with AML remains an unmet need in the field. “It is incredible to me that for approximately 50 years, the only truly effective AML treatment was the combination of cytarabine and an anthracycline, which was effective in only a subset of (typically younger) patients with AML,” she explained. She helped lead the phase I trial of the oral BCL2-inhibitor venetoclax in combination with the hypomethylating agent azacitidine. “[It] led to such dramatic responses that this combination received accelerated FDA approval,” she recalled. Dr. DiNardo currently serves as the coordinating principal investigator for the confirmatory international randomized phase III trial which has recently declared clinically and statistically meaningful improvements in both response and survival with this combination. “The challenge now is trying to determine the best treatment for each particular patient,” she added, praising the increase in scientific understanding of the AML genome and epigenome in the past three years and the approval of multiple targeted therapies.

When thinking of her decision to study hematology, Dr. DiNardo recalled, “We are all impacted by life events in ways we don’t always realize at the time.” In her early school years, two classmates were diagnosed with hematologic malignancies and eventually succumbed to them. Later, she watched her grandmother, who was a vibrant pillar of her family and community, change all too quickly while receiving treatment for aplastic anemia. “I remember being so discouraged hearing the low platelet and various blood count numbers rattled off daily without really understanding their significance, and ultimately feeling so very helpless, frustrated that the ‘best treatment available’ just wasn’t working,” she added. This propelled her to achieve great successes in the field. Along the way, she’s had great mentors, including Drs. Selina Luger, Martin Carroll, and Hagop Kantarjian. The latter taught her that there is always room for improvement, in everything. “His advice is simple and powerful: Never settle.” Dr. DiNardo also considers Drs. Luger and Carroll as huge inspirations. “I wanted to model my whole career after that of Dr. Luger. She is a successful, strong, and only mildly intimidating leader who is loved and respected by colleagues and patients alike … Dr. Carroll taught me the joy of being a life-long learner,” she added, remembering that he taught her to choose a topic she was passionate about and become an expert on it, knowing it inside out. And for those considering a career in hematology, Dr. DiNardo has some motivating words: “I would give them wholehearted confirmation that they made the right choice! This is such a rewarding field.”

Drs. Melnick and DiNardo will be presenting their lectures in December during the virtual 2020 ASH Annual Meeting.

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