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Meeting Report |
1 Division of Cancer Biology, National Cancer Institute, Bethesda, Maryland; and 2 Division of Epidemiology, School of Medicine, University of California, Irvine, California
Requests for reprints: John A. Sogn, Division of Cancer Biology, NCI, Executive Plaza North, Room 5050, 6130 Executive Boulevard, Rockville, MD 20892. Phone: 301-594-8782; Fax: 301-496-8656; E-mail: js150x{at}nih.gov.
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Introduction |
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TopAbstractIntroduction |
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Overarching Themes in the Recommendations
Each Think Tank resulted in a series of important, specific recommendations that are detailed in the full report and will be addressed individually by NCI. In addition, there were recommendations that appeared more than once. All nine Think Tanks strongly recommended continued support for investigator-initiated grants, and especially the R01. Investigator-initiated research has spawned many exciting discoveries worthy of further development in each of the Think Tank areas, and will continue to benefit all cancer research. This summary will concentrate on three overarching scientific and one support-mechanism themes that emerged independently in multiple Think Tanks.
Integrative cancer biology. The first scientific theme common to all of the Think Tanks was the need to support the emergence of integrative cancer biology as a field. To address the complexity of the many interactive and interdependent processes in normal and cancer cell biology, the classical reductionist studies must be complemented by an integrative systems approach. Advanced bioinformatics tools need to be developed and applied to the analysis of a comprehensive "parts list" derived from high-throughput measurements of critical parameters, to construct predictive computational models of the cancer process. Although to date integrative biology has focused mostly on the analysis of signal transduction pathways and other regulatory circuits within a single cell, it is equally applicable to complex processes involving multiple cells and extracellular molecules. For example, a complete characterization of the tumor microenvironment depends on combining high-throughput analytical methods with bioinformatics to generate predictive models of the interactions that drive the microenvironment. This need was stressed by the Tumor Microenvironment Think Tank, but is equally true of all of the other areas explored in the Think Tank process.
The Think Tanks provided strong evidence that this need is an important direction for the Institute to pursue and that its influence will be felt throughout cancer research. Thus, in September 2004, NCI funded a series of Integrative Cancer Biology Programs (http://icbp.nci.nih.gov/), the first organized foray into systems biology in the context of cancer.
The tumor microenvironment. The second overarching scientific theme was the need to understand the tumor microenvironment, its composition and interactions with the tumor. Growth and migration of normal epithelial cells are subject to many levels of regulation by neighboring cells, extracellular matrix, and local levels of soluble signaling molecules. Cancer cells lose critical aspects of these controls, but they lose them gradually and rarely lose them all. Thus, one way of looking at cancer initiation and progression is as an iterative and progressive renegotiation of constraints carried out between a developing clone of epithelial cancer cells and its stromal microenvironment. This perspective suggests two principal lessons. First, attempts to understand tumor behavior or to treat cancers must take into account far more than the intrinsic properties of the malignant cells to be successful. And second, attempts to model tumor behavior must go beyond using tumor cell lines cultured on plastic surfaces, to three-dimensional culture systems and in vivo studies. The Tumor Microenvironment Think Tank provided a detailed blueprint for integrated studies; many of the other Think Tanks emphasized specific aspects of the microenvironment that are often overlooked in overviews of the subject.
While the Think Tank participants emphasized the importance of expanding support for investigator-initiated research of the tumor microenvironment, they also recommended the formation of a network or alliance to encourage cooperative, interdisciplinary studies. Such a network would bring investigators experienced in this area together with scientists with complementary expertise. It would leverage existing individual grant support by providing incremental funding for cooperative projects and for the creation of freely accessible, common resources that would benefit the entire research community. As envisioned by the Think Tank participants, a network would address many current barriers to progress, which are described in detail in the report, but its key goals would be to:
The challenge of comparing the normal and the tumor state. The last overarching scientific theme was not an area of research so much as an approach. Impressive recent advances in understanding cancer biology - many of which were highlighted in the Think Tanks - have opened up an enormous array of promising areas of research. While it is tempting to pursue these opportunities by focusing exclusively on the cancer state, the participants in six of the Think Tanks explicitly recommended against this course of action, emphasizing the critical importance of understanding cancer in the context of normal biology. For example, as a tumor develops, the normal constraints imposed by the microenvironment on cell growth and mobility are gradually loosened. We need to know much more about these normal constraints individually, and about how they are coordinated at a systems level, before the tumor microenvironment can be fully characterized. Normal cellular responses to DNA damage are similarly complex and also must be better described before they can be manipulated for therapeutic benefit in cancer. In tumor immunology, the major advances in understanding that have occurred in the last ten years have come from conceptual advances in immunology as a whole. The critical questions that remain are the same for basic immunology, autoimmunity, chronic infectious diseases and cancer, although the perspectives on the questions differ slightly among these fields. Inflammation in cancer has a marked stimulatory effect on cancer growth not because of its intensity, but because it fails to resolve the way acute, physiological inflammation does. It shares this characteristic with autoimmunity and certain chronic infections. The stem-cell programs of several tissues appear to be involved in cancer progression, but so little is known about the regulatory program within the normal tissue stem cell and the cell-cell interactions of the stem-cell niche that it is difficult to characterize cancer stem cells or to determine the path by which they became transformed. Epigenetics is similarly a young field, in which a great deal of basic knowledge must be accumulated before its role in cancer can be clarified.
The challenge is to identify those elements of these fields that the NCI should attack with its own resources and those where it should work in coordination with other NIH Institutes and other funding agencies. Leveraging of resources is difficult, but necessary. The NIH Roadmap can serve to address some of the cross-cutting scientific issues identified by these workshops, but there remains a great need and an enormous opportunity for a focused effort. It can be anticipated that such research will inevitably yield results that can be broadly applied. While the NIH has some coordinated activities related to human embryonic stem cells, tissue-specific stem cells (with the exception perhaps of hematopoietic stem cells) have received scant attention. Similarly, there is no NIH-wide large-scale project on epigenetics on the horizon, despite its documented importance in many human diseases. The Think Tank recommendations make it clear that catalyzing broadly-sponsored larger-scale studies of some critical cross-cutting biological issues must be a high priority to provide the necessary context for progress against cancer.
Other common scientific themes. Two other commonly raised issues, though less pervasive than the three described above, deserve mention. Inflammation was recognized as important enough to deserve its own Think Tank, but it was surprising how prominent a role it occupied in other Think Tanks. This suggests that it needs an even more prominent role than had been envisioned in initiatives to study the tumor microenvironment, where inflammation is a nearly constant finding. A related common theme was the role of microbial flora as a cofactor in tumor development. While biological carcinogenesis, with an emphasis on cancer caused by viruses, has always been supported within NCI, examination of a cofactor role for microbes that are not directly transforming has lagged behind. This is one of several areas that bridge cancer biology and etiology.
Mechanisms to foster collaborative, interdisciplinary research and training. The final overarching theme dealt with the mechanisms through which NCI supports research. NIH grants, built around the R01 traditional research grant, have been the engine of creativity that has brought us to the current exciting point in cancer research. The Think Tank participants uniformly acknowledged the past and continuing importance of R01 grants. During the Think Tanks, however, they focused on needs that are difficult or impossible to meet through this mechanism. These were generally large-scale efforts, especially those that required input from scientists in diverse disciplines. The Tumor Microenvironment Network, described above, is an example of the recommendations, but similar networks were suggested in immunotherapy, stem-cell research, epigenetics, etiology and susceptibility. The Think Tank panelists and the great majority of the scientific community want to see support for investigator-initiated research remain strong, but it is clear that a new balance must be struck that permits both smaller scale individual and larger scale collaborative/interactive approaches to cancer biology to flourish where they are most productive.
In some cases, less formal (and smaller scale) resources for collaboration were recommended. Many of the recommendations involved more coordination rather than direct research support. These recommendations were made because there are very few investigator-initiated NIH funding mechanisms that can support any of these varied activities. Critical problems in cancer research and other areas of biomedicine increasingly require a variety of expertise and/or the sharing of data or reagents in a manner that is not facilitated or sometimes even possible when support comes exclusively from grants to individual principal investigators. Constraints on collaborative and interdisciplinary research also exist at research institutions. Rigid departmental structures, intellectual property policies and concerns about indirect costs can make some types of research more difficult. With sufficient resources, these recommendations could all be addressed through NCI-directed mechanisms such as contracts, supplements and workshops. What may be needed, however, is a highly flexible, permanent program open to investigator-initiated applications to support modest-scale, collaborative, interdisciplinary research efforts.
Each recommendation for an interdisciplinary research program was accompanied by a recommendation for a program that would train students, postdoctoral fellows and established investigators to take optimum advantage of the opportunities such a program would create. Three types of suggestions about interdisciplinary training were made during the Think Tanks. One was to incorporate training into large-scale interdisciplinary initiatives. This was done in the Integrative Cancer Biology Programs. The second was to place some leverage back in the hands of graduate students by inaugurating individual pre-doctoral fellowships in which the range of subdisciplines and the mentor(s) could be determined by the graduate fellow and not the institution. The third was to reserve a portion of NCI postdoctoral training grants for explicitly interdisciplinary programs. While institutions are moving to respond to the need to change training paradigms, the Think Tank process made it clear that NCI must work to facilitate and accelerate such change.
Other common support issues. Support for technology development, in general, appears to remain a challenge despite the addition of many new programs in recent years. Think Tank participants consistently reported limitations in funds for reagent preparation (e.g., monoclonal antibodies), model development (both genetically engineered animals and complex, three-dimensional tissue cultures), and state-of-the-art imaging. Funding for critical resources needs to be factored into plans in many areas, but it was also surprising that in some instances Think Tanks recommended that NCI make available resources, including reagents, databases, animals and facilities, that are already available. This indicates that more effort needs to be put into ensuring that all members of the cancer research community are aware of the resources NCI currently provides. If there are problems of quality or access with existing resources, these need to be evaluated as well.
Specific Recommendations of the Individual Think Tanks
In addition to the overarching themes of the Think Tanks, each one provided recommendations specific to its area. The principal recommendations of the individual Think Tanks were as follows:
Concluding Remarks
The Think Tanks provided a substantial blueprint for NCI actions in support of cancer biology. Their recommendations included a major initiative in integrative cancer biology, which has been funded, and will serve as the basis for a series of major initiatives related to the tumor microenvironment. Smaller initiatives of several types, responsive to specific recommendations from individual Think Tanks, have appeared or are under development. Current and planned initiatives have to take into account the fact that the NIH grants system, which continues to be an efficient engine of discovery for individual investigators, provides limited opportunities for those who want or need to work in larger groups, particularly those that are interdisciplinary in nature.
As much as the Think Tanks focused on needs in cancer biology, they provided powerful illustrations of the interdependence of different areas of cancer research. Tumor immunology, as the report demonstrates, can no longer be discussed without considering immunotherapy. As modern, clinical immunotherapy has had increasing impact, it has provided more valuable feedback to guide research in basic immunology. In turn, the path to translational development for basic discoveries has become clearer (although, as the report also illustrates, this path is littered with obstacles). Productive research in cancer susceptibility requires a familiarity with human population studies and mechanistic cancer biology, in particular the use of genetically engineered animal models of cancer. In turn, susceptibility information directly informs prevention research. Inflammation is equally cross-cutting, uniting cancer biology, treatment and prevention. Many other examples could be cited. Cancer biology has always had strong ties to many other disciplines, inside and outside the cancer research community. The Think Tanks show that these ties contribute to the continued intellectual vitality of the field.
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Acknowledgments |
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We thank Robin Brown for outstanding assistance in organizing the Think Tanks.
Received 5/25/05. Revised 7/ 8/05. Accepted 8/ 8/05.
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