Mapping the Road to Progress in Lymphoma Research: An Update from the ASH Meeting on Lymphoma Biology

To review the state of science in lymphoma biology, the American Society of Hematology (ASH) organized the ASH Meeting on Lymphoma Biology in August 2014. More than 350 lymphoma experts from around the world convened in Colorado Springs to share cutting-edge findings in the field and set the course of future lymphoma research.

“One of the goals of this meeting was to work together as scientists to develop a roadmap for lymphoma investigation — determining where the roadblocks were that were preventing us from making transformative breakthroughs, and then determining how we could overcome these bottlenecks,” David Weinstock, MD, co-chair of the Meeting on Lymphoma Biology, told ASH Clinical News. “I think we made great strides at this year’s meeting.”

Those discussions have now been consolidated into a “roadmap” for future discovery in lymphoma biology, recently published as a Letter to the Editor in the March 26, 2015, edition of Blood, and authored by Dr. Weinstock and members of the Meeting on Lymphoma Biology Steering Committee. This map could inform allocations for increasingly competitive national funding, as well as direct advocacy efforts from ASH and other organizations.

The correspondence outlines the major priorities in lymphoma discovery and translation – both in infrastructure and research.

The TABLE below outlines some of the top priorities identified by the Steering Committee. For the complete “roadmap,” visit www.hematology.org/lymphoma-roadmap.

Filling Knowledge Gaps

“Investigation of individual lymphoma subtypes is largely limited by the same considerations that affect many other tumors,” Dr. Weinstock, from the Dana-Farber Cancer Institute, and colleagues write in their correspondence. These factors include:

  • inadequate numbers of representative cell lines and in vivo models,
  • inadequate characterization of the genetic landscape of each subtype
  • limited interest in rare subtypes with poorly understood pathobiology from the pharmaceutical industry
  • insufficient collaboration across centers, which limits both expertise and resource availability

The roadmap addresses these inadequacies in several suggested approaches, from developing better disease models to translating those models into the identification of novel compound activities in lymphoma.

“Functional approaches are needed to distinguish driver events and to define critical dependencies that can be exploited therapeutically,” the authors continued, noting the importance of creating new prognostic models that incorporate predictive biologic and clinical factors.

An Effort Needing Broad Support

“We outline a roadmap for discovery and translation in lymphoma that focuses on improving the understanding of disease biology across the broad diversity of subtypes,” the authors explained, while noting that progress also needs to be supported across the medical community.

“The fundamental goal [is] extending effective treatment to all patients with lymphoma,” they continued. “Achieving that goal with maximum efficiency and expedience will require a broad and collaborative effort between researchers, patients, funding agencies, pharma, and advocacy groups.”

That collaboration includes hearing the thoughts and concerns of ASH membership. The “Roadmap for Discovery and Translation in Lymphoma” is available for comment at: www.hematology.org/lymphoma-roadmap.


TABLE. Priority areas for lymphoma discovery and translation, divided into Infrastructure and Research areas.

Examples of specific targets in each priority area are provided to guide funding and advocacy. The Table is not intended to be comprehensive across all aspects of lymphoma-related research, but instead to serve as a focused catalog of high-priority areas.

Priority Area Examples for Specific Targets
Infrastructure
Model developmentDevelop disease models, including cell lines, PDXs, GEMMs, and zebrafish models. Reliable models are essential tools for interrogating disease biology as well as experimental therapeutics.
  • Establish ≥5 cell lines for each lymphoma subtype and for each common genetic aberration, with characterization by RNA and exome sequencing.
  • Establish ≥5 in vivo models for each lymphoma subtype and for each common genetic aberration, with characterization by RNA and exome sequencing.
Advocacy and developmentOrganize patient advocacy to support research. Advocacy promotes fundraising, sample collection, government lobbying and disease visibility, while aligning research priorities with community goals.
  • Establish educational and interactive websites for each lymphoma subtype.
  • Establish lymphoma advocacy groups through existing organizations (e.g. ASH, Leukemia and Lymphoma Society, Lymphoma Research Foundation).
Research
Experimental therapeuticsIdentify novel compound activities in lymphoma using cell line and in vivo models. Like genetic screens, compound screening can establish novel targets as well as mechanisms of action.
  • Screen existing bioactive libraries against all relevant lymphoma cell lines.
  • Establish biomarkers for de novo sensitivity and resistance using genomic and other data.
Patient stratificationDevelop strategies to identify and target high-risk subsets of patients. Patient stratification can expedite clinical trials by targeting patients with specific biology.
  • Establish next-generation prognostic indices that incorporate genomics and other data for individual lymphoma subtypes.
  • Develop a therapeutic strategy to target MYC in DLBCL.
Immune therapiesTurn the power of the immune system against lymphoma. This includes the identification of synergistic combinations of immune therapies, targeted therapies and chemotherapy.
  • Enhance the effectiveness of therapeutic monoclonal antibodies.
  • Combine therapeutic antibodies and small molecules with agents that block immune checkpoints.
Normal lymphocyte developmentDefine the common features and unique traits of specific lymphoid malignancies in comparison with their developmentally-related normal lymphoid counterparts.
  • Define all molecules necessary to initiate and sustain the germinal center response.
  • Define all key protein-protein interactions and post-translational modifications that regulate B-cell receptor signaling.
Clinical translationDevelop robust biomarkers that can be translated into the clinical laboratory using platforms suitable to routinely available formalin-fixed, paraffin embedded biopsy material.
  • Perform studies that integrate the mutational landscape and are powered to identify/validate molecular correlates of survival.
  • Develop transcriptional, epigenetic and/or metabolomic signatures downstream of genetic aberrations that can be tested using large patient cohorts who received uniform therapy.

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