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Leukemia Stem Cells, Heterogeneity, and Metabolism

September 12–15, 2019

Chaired By

 Martin Carroll, MD of University of Pennsyilvania
 Craig T. Jordan, PhD of University of Colorado
 Aaron Schimmer, MD, PhD of Princess Margaret Cancer Centre

Meeting Description

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a generally poor outcome. Despite the ability to achieve remission with aggressive chemotherapy most patients relapse and ultimately succumb to their disease. Relapse disease is frequently due to chemoresistant leukemia stem cells (LSCs). Thus, new therapeutic approaches that are less toxic and better tolerated by older and frailer individuals are required. Moreover, new therapies that target the LSC population to induce cell death or promote their differentiation into more mature cells are required. The last few years have seen tremendous advances in our understanding of LSC biology and potential new therapies to target these cells. Therefore, we believe this is a critical time to convene a group of experts to synthesize new therapeutic directions. Thus, our proposed Forbeck conference will bring together a multi-disciplinary group of leading experts (basic scientists, translational scientists and clinical trialists) to design compelling strategies for translational/clinical studies.

Meeting Summary

From September 12th to 14th, 25 experts with diverse point of view met to present data and discuss the theme of leukemic stem cells. The meeting was highly successful in bringing together not simply the known experts in the field but individuals with backgrounds in leukemic research, basic cellular biochemistry, clinical medicine and others to discuss and challenge idea’s in the field. The meeting was highly interactive and lively.

Why was this meeting relevant now?
Although there have been recent advances leading to less toxic therapies for acute myeloid leukemia (AML), the survival of patients after a diagnosis of AML is still poor. This meeting allowed researchers to take a “deep dive” into two discrete area’s of AML pathogenesis where there has been significant new recent information but also significant controversy. First, the investigator’s considered the title theme of leukemic stem cells vs leukemic heterogeneity. It was previously thought that all leukemia cells from a given individual were highly similar to each other. However, it has become clear from numerous lines of evidence that there are significant differences between an individual’s leukemic cells that create a barrier to cure. In one model, cells that are similar to blood stem cells but have leukemic properties are resistant to chemotherapy. Significant discussion was had on how these cells can be characterized, their defining features, whether they are the target of novel therapies, etc. In the stem cell model, these leukemic stem cells give rise to all other leukemic cells. In an alternative model, leukemic cells vary from each other randomly. This random variation may occur through changes in the DNA (genetic variation), the molecules that regulate gene expression (epigenetic variation) and others. Significant discussion of recently described genetic variation was had with proposals and discussions about how to target this variation before it leads to therapeutic resistance.

What came out of this meeting? Conceptual, collaborations any papers or experiments.
Significant conceptual change in the impact of studies of leukemic cell metabolism did occur. One of the recent surprises in leukemic therapy is the success of the drug, Venetoclax, when used in combination with drugs known as hypomethylating agents. Venetoclax is thought to act through inhibition of a cell survival protein called Bcl2. However, the biologic studies of the role of Bcl2 in AML biology have shown conflicting results. An exciting session occurred where three investigators showed work that suggests either that Bcl2 has a previously unknown function or that Venetoclax may work through a different mechanism than proposed. In particular, the three groups have data that Venetoclax may inhibit the leukemic cells machinery for energy production, a biochemical process known as oxidative phosphorylation. Data was presented that combining venetoclax with other agents that further cripple this process is even more effective at killing leukemic cells in the laboratory than combining it with hypomethylating agents. Ideas for how to translate this into clinical trials were discussed. Overall, a major impact of the meeting on this diverse audience was to increase the understanding of the critical role of altered cell metabolism to leukemic development. Additionally there was significant discussion about developing new methodologies for studying cell metabolism in primary human AML cells. We believe that these discussions will quickly lead to new combination treatment approaches that take advantage of this new insight.

What do you see developing in this field from this meeting?
Several developments are likely to result from this meeting. All meeting attendee’s expresses great enthusiasm for the open, interactive “give and take” of the meeting format. Several of the attendee’s organize larger meetings and there were discussion about how to bring this format into these other meetings.

With regards to scientific and therapeutic progress, as noted, significant attention was spent discussing ways forward for new metabolically directed drug combinations in AML. New collaborations have actually already been initiated based on interactions at the meeting.

How does this impact patients today?
As noted above, the discussion of leukemic cell metabolism and studies of the mechanism of Venetoclax activity in AML are likely to be highly impactful. In general, cancer doctors work to develop therapies by combining agents that are toxic to cancer or leukemia cells without causing an increase in side effects. The great breakthrough it was agreed of the Venetoclax-hypomethylating agent combination is that leukemic control or remission can be achieved without a high level of toxicity. Data at the meeting demonstrate that this is not likely to be curative however for the majority of patients. Thus, the focus on adding new agents to this recently developed and lower toxicity regimen is likely to lead to new approaches towards curative therapy. In fact, some such trials have already been opened at the researchers sites and ideas were discusses about how to interpret those trials as they are performed.

Forum Participants

Julie Aurore-Losman, MD, PhD
Dana-Farber Cancer Institute

Shruti Bhatt, PhD
Dana-Farber Cancer Institute
 Forbeck Scholar

Martin Carroll, MD
University of Pennsylvania

Steven Chan, MD, PhD
Princess Margaret Cancer Center

Jean Emmanuel Sarry, PhD
Cancer Research Center of Toulouse - Inserm

Maria Figueroa, PhD
University of Miami

Monica Guzman, PhD
Cornell Medical College

Takahiro Ito, PhD
University of Georgia

Craig Jordan, PhD
University of Colorado

Harry Leighton Grimes, PhD
Cincinnati Children's Hospital

Ross Levine, MD
Memorial Sloan Kettering

Ravi Majeti, MD
Stanford University

Emmanuelle Passegue, PhD
Columbia University

Dan Pollyea, MD
University of Colorado

Aaron Schimmer, MD, PhD
University of Toronto

Danielle Shin, MD, PhD
Stanford University
 Forbeck Scholar

Liran Shlush
Weizmann Institute of Science

Uli Steidl, PhD
Albert Einstein University

Zuzana Tothova, MD, PhD
Dana-Farber Cancer Institute
 Forbeck Scholar

Jennifer Trowbridge
The Jackson Laboratory

Peter van Galen, PhD
Massachusetts General Hospital
 Forbeck Scholar

Paresh Vyas
University of Oxford