Group B: Mechanisms of Tumor Development or RecurrenceThere are four questions in this group.
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Why do second, independent cancers occur at higher rates in patients who have survived a primary cancer than in a cancer-naïve population?
Background: Second cancers are a major problem for cancer survivors. Grouped as a single outcome in the Surveillance Epidemiology and End Results (SEER) database, second cancers rank fourth in overall cancer incidence and are often associated with poor outcomes. However, researchers have not taken full advantage of this population to study risk factors and mechanisms. The influence of prior therapeutic interventions (including chemo- and radio-therapies) and somatic mutations in this population has been studied to some degree. However, the extent to which underlying genetic predispositions, environmental factors, and life-style behaviors influence risk remain relatively underexplored. It is likely that at least some of the contributing risk factors and mechanisms would be relevant to all cancer patients, not only those with second independent cancers.
Feasibility: Given the high risk of these developing in cancer patients and their involvement with medical oncology personnel, it should be substantially easier to monitor cancer survivors for the development of a second cancer than to observe healthy individuals for the development of a first cancer. Cancer survivors are often followed prospectively for treatment response and complications, as well as disease progression. Technologies that identify somatic alterations can be integrated with genome-wide annotation of germ-line DNA to investigate the relationship between genetic susceptibility in high-risk individuals and second cancers. With the advent of new, more efficient technologies, it is feasible to broaden these efforts to large-scale clinical trial studies. Efforts to capture clinical, epidemiological, and therapeutic data could also be centered on the development of large-scale cohorts of cancer survivors at risk for second cancers. Because of their heightened risk of cancer, this population of patients may be more motivated, and therefore well suited, for prospective prevention studies, such as chemoprevention or behavioral modifications.
Implications of success: Studying patients who have had primary cancers for the development of second cancers could help uncover pathogenic mechanisms of both cancers, including shared etiologic pathways and therapy-related risks. These insights are likely to inform new strategies for preventive interventions.
What molecular and cellular events in the tumor microenvironment (for example, the local immune response) determine if a tumor at the earliest stages of malignant transformation is eliminated, stimulated for further development, or made indolent?
Background: It is now thought that the tumor microenvironment plays conflicting roles during the earliest stages of cancer development. For example, the immune response may have both the capacity to eliminate transformed cells or promote their tumorigenic potential. Recent reports have suggested that within hours after an oncogenic event, transformed cells secrete danger signals that attract innate immune cells. The role of early immune responses is not well understood. Importantly, the nature of the immune response could have profound consequences in determining whether tumors are eliminated or allowed to progress. It is likely that other interactions between the developing tumor and its microenvironment may also have both positive and negative roles in how the tumor develops. This Provocative Question seeks to determine what critical events in the microenvironment at this early stage determine whether a pre-emergent tumor is eliminated or allowed to progress.
Feasibility: An important prerequisite for studies in response to this question will be the selection of appropriate systems to study the tumor microenvironment during the very first stages of transformation. Genetically engineered mouse models might provide a good system to begin such studies or there may be a well understood human tumor development system that could be used. Characterization of well-known features of the tumor microenvironment or tumor immune response mechanisms at these earliest stages may provide a useful starting point for studies. These stages may also lend themselves to high-throughput profiling or other omic-style studies to help characterize these events.
Implications of success: Understanding the earliest responses within the microenvironment to the emerging tumor cell promises to be one of the best points to influence the course of malignancy development. The ability either to manipulate these responses towards elimination or to block any enhancement of tumor development could be used to identify new targets for therapy or for prevention.
What mechanisms initiate or sustain cancer cachexia, and can we target them to extend lifespan and quality of life for cancer patients?
Background: Cachexia, or wasting syndrome, is a common, devastating condition seen in many patients with late stage cancer. When present, cachexia will almost certainly be a contributor to death. Although there have been several previous periods of intense research focus on cachexia, we still know little about what signals its initiation or maintenance. This Provocative Question calls for new studies on the biology of cachexia, the signals that are important for its regulation, and the reasons why it resists reversal.
Feasibility: Modern methods of biological characterization promise to generate new information about the process and control of cachexia. Omic studies of affected tissues and of tumors themselves may provide new clues to its origins and the inability to reverse its course. All approaches open to modern in vivo biological studies should be available to characterize and study cachexia. New animal models may be developed that would provide reproducible systems to study this process. It may also be possible to establish genetic, RNAi, TALEN, chemical biology, or other screening strategies to look for essential features of wasting and its regulation.
Implications of success: Advances in our knowledge about the causes and biology of cachexia will lead to better understanding of this late stage cancer event. Whether any of the causes or consequences of cachexia will be treatable remains unknown, but any advances will depend on intense study of its biology.
What methods can be devised to characterize the functional state of individual cells within a solid tumor?
Background: Detailed tumor characterization through various omic-style studies revealed an unexpected degree of cell heterogeneity within each tumor. It now appears that each tumor is composed of a vast array of cells that have accumulated genetic and epigenetic changes during tumor development. Some of these changes are thought to be essential to key tumor properties, e.g., for cell survival, cell division, or range of therapeutic response, but others are almost certainly the so-called passenger changes that do not contribute to individual cell phenotype. Importantly, the array of different cells within the tumor contributes to functional heterogeneity as seen by enhanced evolution in response to changing selective pressures, escape from therapeutic interventions, and development of deadly metastatic potential. Methods to characterize cell functional heterogeneity have not been widely used to characterized the individual cells within solid tumors. We need to be able to identify and understand the features that promote further tumor development or therapeutic response. While methods to determine single cell phenotypes or genotypes are rapidly advancing and have been used to characterize single cells in culture and some blood tumors, it is essential to apply these methods to single cells within solid tumors. This Provocative Question seeks to stimulate technology advances of all types to depict and study the functional heterogeneity within solid tumors. Of note, this Provocative Question is limited to solid tumors and not blood tumors where cell separation and characterization methods already exist to study heterogeneity.
Feasibility: Major topics of current interest are new methods for in-depth analysis of single cells. Successful applications should feature some method of deep characterization of single cells combined with an approach to explore the features of single cells directly in a tumor, in tumor explants, or in cells isolated from solid tumors. It may be possible to study individual cells through in vivo imaging of the tumor in situ or in tumor explants to gain an understanding of tumor heterogeneity at a single-cell level. Another general approach might include the production of large panels of cell lines using newly developed immortalization strategies that would recapitulate the heterogeneity within one tumor. Isolation and single-cell cytometry may also be useful in some cases. The goal of successful applications should be to characterize individual tumor cells in sufficient detail that the features described through the single-cell analysis can be linked to functional phenotypes of whole tumor activities.
Implications of success: Understanding the functional heterogeneity of tumors provides fundamental knowledge that should lead to better understanding and predictions of tumor responses to any stress and to better understand the steps of tumor development. Methods developed in response to this question will push the technical abilities to find distinct functional subsets of tumor cells, and promise to greatly expand our capabilities of understanding the details of different cell phenotypes within a tumor.