Group D: Cancer Therapy and OutcomesThere are four questions in this group.
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What molecular properties make some cancers curable with conventional chemotherapy?
Background: Although chemotherapy is often effective, it is rarely curative. However, it is well established that certain childhood cancers, some adult disseminated cancers, and rarely some adult solid tumors can be completely cured with chemotherapy, even with drugs that are often of much less value in other settings. While these responses are wonderful when they occur, there is little understanding of the underlying mechanisms that might explain why these cancers can be cured with chemotherapy. This Provocative Question seeks to understand what molecular properties of tumors make them curable by conventional chemotherapy.
Feasibility: This question has largely been ignored since it was recognized, decades ago, that such tumors could be cured by standard chemotherapeutic strategies. New methods are available for studying the biology of these “curable” cancers and for exploring the mechanisms by which the effective drugs work.
Implications of success: If we could identify the properties of cancers that render them susceptible to eradication by chemotherapy, we might better understand how certain therapies work, contemplate converting relatively insensitive tumors to highly sensitive ones, or develop new approaches to the treatment of intransigent malignancies.
What features of standard-of-care therapies enhance or inhibit the efficacy of immunotherapy?
Background: Combining two or more therapies is one of the most common and effective methods to increase the effectiveness of cancer treatments. Looking for new combination therapies has become increasingly important as new targeted treatments have led to the generation of resistant tumors after continued therapy. Most approaches to test new combinations have relied on empirical assays that combine various small molecule inhibitors with one another or with chemotherapies. These approaches are being augmented by others that rely more deeply on rational strategies and use detailed knowledge of how different therapeutic outcomes can be best combined. Given the recent advances in the use immune modulatory therapies, i.e., those that rely on augmenting the ability of the host immune system to mount an immune response against the tumor such as stimulatory cytokines, activators of co-stimulatory molecules, immune checkpoint inhibitors, immune maturation agents, and therapeutic vaccines, the concept of combining these approaches with targeted or chemotherapy has begun to be considered and tested. However, we have little knowledge of how the results of current standard-of-care treatments for various malignancies will enhance or inhibit the addition of these immune modulatory therapies. This Provocative Question seeks to understand how best to combine these therapeutic approaches.
Feasibility: Any tumor model that shows a favorable response to an immune modulatory agent could be used to study how this response might be altered by other cancer therapeutic agents. We leave it to the ingenuity of applicants to choose how such agents might be selected for comparison. Any molecular events that are altered by potential agents could provide useful intermediate markers to measure collaborative effects that could predict changes in tumor response.
Implications of success: Extending the range of tumors that might respond to immune modulatory agents or the strength of their response may signal useful approaches that could be studied in subsequent clinical trials. More information about how any two agents enhance or inhibit one another will expand our understanding of the principles behind effective combination therapy.
Do tumors evolve common features that could act as new therapeutic targets when they metastasize to the same secondary site?
Background: When tumors metastasize, their evolutionary development continues as they respond to the selective pressures at the sites of colonization. Recent studies have begun to catalog the molecular differences among different metastases that arise from the same primary tumor and variations seen between primary tumors and their metastases. How do the selective pressures of a specific metastatic environment influence each tumor’s development? Can common events be discerned among these changes? Such common events may be limited to metastases that arise from very similar origins or with very similar mutational histories. Alternatively, selective pressures of certain tissues might impose barriers that lead to very common solutions. Any common solutions, whether restricted to tumors of similar heritages or restricted to certain sites of metastasis, can be used to identify new targets for therapeutic attack.
Feasibility: As the molecular, cellular, and functional characterization of metastases increases, a vast amount of data will be available to examine for similarities. Similarities between metastases found at the same site could be based on any number of variables, including similar sites of primary tumor origin, similar sets of driver mutations, or similar local microenvironments. It is also possible that data from more than one set of variables may need to be aligned to allow similarities to become obvious.
Implications of success: Similar features would provide clues to identify a new class of potential targets for drug development.
What are the mechanistic bases for differences in cancer drug metabolism and toxicity at various stages of life?
Background: It is well understood that patients process drugs in different ways at different stages of life. However, we know little about what accounts for these differences. How does liver or kidney enzymology change as patients age? What molecular changes in drug uptake and metabolism can be rigorously determined and can we use these changes to understand how to adjust therapeutic decisions, adjust doses, or change regimens to better link cancer therapies to patient age?
Feasibility: Drug metabolism studies have not yet linked findings to the various physiological differences associated with aging. The same methods currently used in cancer drug metabolism studies could be combined with our growing understanding of the molecular changes detected in aging individuals. Similar strategies could be used to understand other differences related to patients’ ages.
Implications of success: The definition of key steps in drug metabolism that change with age could lead to simple tests to measure these responses and then better tailor drug delivery to cancer patients at their actual stage of life.