Lymphoma Experts Set Priorities for Research; Seek More Input

Abstract

FigureA group of leading lymphoma researchers have issued a list of priorities to improve the current research paradigm and identify future investigational needs. In a Letter to the Editor in Blood (2015;125:2175-2177), David M. Weinstock, MD, Associate Professor at Harvard Medical School and an attending physician in the Medical Oncology Service at Dana-Farber Cancer Institute, and 11 other lymphoma experts, outline a plan to better address current shortcomings in research approaches and what can be done to improve investigations and collaborations. The recommendations are the result of a collaborative initiative by the American Society of Hematology, which started the project during a forum on basic and translational science relevant to lymphoma that began at the first ASH Meeting on Lymphoma Biology, held last August. The authors of the letter, members of the meeting's steering committee, were asked to create a research “roadmap” for future efforts in order to better guide funding, especially requests from the National Institutes of Health, as well as advocacy by ASH and other associated organizations. “Our goal is to help inform future research directions and funding decisions by partners at government agencies and in the private sector,” said Weinstock, Co-chair of the ASH initiative. Although almost half of all blood cancer cases are lymphomas, of which there are numerous unique disease subtypes, recent advances have led to better characterization on how lymphoma cells proliferate and interact with other cells and tissues, leading to powerful, targeted therapies with fewer side effects than approaches in the past.DAVID M. WEINSTOCK, MD. DAVID M. WEINSTOCK, MD: “The roadmap outlines our most pressing needs, that if not addressed will stand in the way of transformative changes in how we study and treat lymphomas.Nonetheless, limitations in research infrastructure, funding, and collaborative approaches present potential challenges in the development of better treatments. The report outlines key priorities for research and infrastructure to improve the understanding of lymphoma biology across its diverse subtypes (see box on next page). “The roadmap outlines our most pressing needs, that if not addressed will stand in the way of transformative changes in how we study and treat lymphomas,” Weinstock said. “We want to help facilitate and guide collaborative efforts toward the most high-impact areas that might lead to more rapid development of new treatments.” According to the panel, investigation of individual lymphoma subtypes is largely limited by many of the same issues with other tumors, including inadequate numbers of representative cell lines and in vivo models, including patient-derived xenografts and genetically engineered mouse models; inadequate characterization of the genetic, epigenetic, transcriptional, proteomic, and metabolomic landscape of each subtype; limited interest from the pharmaceutical industry in rare subtypes with poorly understood pathobiology; and insufficient collaboration across centers. These shortcomings are made more complicated by biologic heterogeneity within each lymphoma subtype, and preclinical studies addressing this heterogeneity will require large numbers of samples and/or models for stratifying patients and validating potential biomarkers, according to the letter. Addressing Barriers “So far the response has been somewhat muted,” Weinstock said. “We are inviting clinicians, scientists, advocates, and patients to weigh in on this so that it reflects the input of everyone in the community.” The panel will share its findings on priorities with funding agencies, advocacy groups, and others who can help address the challenges identified. Weinstock said that because of the current lack of a coordinated research approach, many lymphoma patients have poor outcomes, including those with mantle cell lymphoma, subtypes of peripheral T-cell lymphoma, and lymphomas that harbor specific genetic markers. Moreover, the consequences of most genetic mutations remain unclear, making it necessary to develop functional approaches to distinguish driver events and more clearly define critical dependencies that can be exploited therapeutically. “The most important priority is to develop model cell lines in vivo and cell lines in lesser and more common subtypes,” he said. Another high priority is developing new prognostic models that incorporate biologically informative predictive factors along with clinical factors to enable patient selection for clinical trials and highlight the biological pathways and mechanisms that can influence therapeutic response. “Comprehensive investigations of larger collections of clinically annotated patient samples are needed to identify additional determinants of treatment response, and these predictive features will inevitably shift with new therapies,” he said. “A lot of this research is now being done at academic centers, but because they rely on outside funding there are proprietary reasons to protect their findings—so many institutions are research silos. Once findings are published, much of the data is available to the oncology community, and most cell lines are already in circulation. This is a significant challenge and a major roadblock.” ‘Difficult to Get Everyone on the Same Page’ There is some skepticism that this will change any time soon, Weinstock admitted. “It is difficult to get everyone on the same page. With some subtypes there are fewer than 1,000 patients, so this is not just hysteria.” “There have been efforts like this before, but this is the most comprehensive. Targeted immunotherapy has shown promise against some lymphomas and others are being tried. I can almost see the endgame.” ‘A First Step’ Asked for his perspective, Jason Westin, MD, Assistant Professor in the Department of Lymphoma/Myeloma at the University of Texas MD Anderson Cancer Center, said: “I think this is an important first step in getting the lay of the land. Without a consensus it is very difficult to get down to the bare bones of what needs to be done to get big data for cooperative studies.” Westin has been involved in research on diffuse large B-cell lymphoma; development of systems to identify novel, optimal therapeutic combinations for individual patients, as well as drug synergy, additivity, and antagonism, scale free networks and their role in cancer therapy; and development of highly sensitive disease monitoring methods. In an article titled “Busting Robustness: Using Cancer's Greatest Strength to Our Advantage,” published in January in Future Oncology (2015;11:73-77), Westin posed the question of what complex networks, such cancer cells, airplane flight patterns, and the Internet share in common. The answer? All have both remarkable robustness and great vulnerability. “Complex networks follow remarkably similar patterns across seemingly unconnected fields, and it is possible that cancer researchers could thus learn from the advances in complex network theory,” he wrote, noting that very limited but coordinated specific targeting of the most critical parts of such networks can have dramatically outsized effects.”JASON WESTIN, MD. JASON WESTIN, MD: “Developing a coordinated and systematic approach is very difficult—but the more we cooperate, the more we understand how to do it.”He said that developing a coordinated and systematic approach is very difficult—“but the more we cooperate, the more we understand how to do it. All of the authors of this plan are really leading researchers in lymphomas, but the proof is in the projects that may result.” He said that creating central repositories of tissues and cells in patients who do well or not is especially important for future research because most studies undertaken have relatively small sample sizes. “Sharing this data and samples in an open-format central repository would be huge,” especially because of the increasing robustness of data from tissue samples fixed in formalin. Even so, Westin continued, it will take some effort to build this due to potential resistance from individual research groups at institutions with a stake in protecting their findings until publication. “This is one main stumbling block as I see it, but it could be done if such data, especially genomic information about patients, were somehow protected.” There are a number of good precedents for such an approach, especially the Cancer Genome Atlas at NIH, he noted: “I would really like to change this. I am not sure it will happen tomorrow, but the more we try, the more value will become apparent. This roadmap lays the groundwork and it may take years, but ultimately it is the patients who will benefit.” Priorities The plan identifies the following priorities in infrastructure and research: Infrastructure Develop an adequate number of disease models for each lymphoma subtype; Establish a central repository of biospecimens, cell lines, and in vivo models with open access; and Organize patient advocacy to support research. Research Catalog how lymphoma cells differ across disease subtypes; Better define and identify mutations and other abnormalities associated with the disease; Develop strategies to identify high-risk patients who may benefit most from clinical trials; Enhance efforts to use immune therapies to cure lymphoma; and Better understand how lymphoma cells communicate with normal cells. From Weinstock et al: Blood 2015;125 (13):2175-2177 Coauthors The other coauthors of the Roadmap letter in Blood are: Riccardo Dalla-Favera, Randy D. Gascoyne, John P. Leonard, Ronald Levy, Izidore S. Lossos, Ari M. Melnick, Grzegorz S. Nowakowski, Oliver W. Press, Kerry J. Savage, Margaret A. Shipp, and Louis M. Staudt.