"Translational Science" is an overarching term encompassing the steps that must be taken to move or "translate" a new detection or diagnostic method or preventive or treatment intervention from the laboratory bench to its ultimate clinical use for patients. As we learn more about how prostate cancer develops and progresses, a number of promising approaches to prevention and treatment have been identified. These include inhibiting angiogenesis (the formation of tiny blood vessels that feed the tumor); inhibiting steps in the cell cycle in order to promote the death of cancer cells; and manipulating the immune system. However, to capitalize on this new knowledge, we will need substantial and sustained investment in the infrastructure to allow development and testing of important emerging basic science discoveries into clinically useful products.
Because "Translational Science" is an extremely broad area, our Prostate Cancer Research Plan in Translational Science is necessarily diverse, covering such things as:
Discovery of new prostate cancer treatments and preventive agents based on the molecular mechanisms that underlie prostate cancer initiation and progression;
Procurement and dissemination to the research community of well-characterized prostate tissue;
Establishment of the molecular profiles of premalignant changes and of cancers at different stages of development for the purpose of improving tumor classification;
Development and validation of new biomarkers that distinguish between aggressive and indolent prostate cancers;
Enhancement of the capabilities of imaging technologies to identify the biological properties of a precancerous or cancerous cell that will predict clinical behavior; and
Enhancement of the NCI's Specialized Programs of Research Excellence to facilitate translational research.
Strategies & Plans: Drug Discovery
Goals:
Base discovery and clinical testing of new agents for cancer on the molecular mechanisms that underlie neoplastic transformation, cancer growth, and metastasis.
Fund the rapid movement of agents from academic and other laboratories into the clinic.
Initiatives:
Rapid Access to Intervention Development (RAID) Program
This program enables investigators to begin clinical trials with novel molecules discovered in academic laboratories. It does this by giving academic investigators access, on a competitive basis, to NCI's preclinical drug development resources and expertise. Investigators having molecules that hold promise for cancer treatment but without access to the development resources required for initiation of clinical studies are invited to submit applications twice a year. Those selected for support are provided assistance with any necessary development steps to enable IND filing and the initiation of proof-of-principle clinical trials. For 1999 the goal is the development of three to five new therapeutic agents, each relevant to prostate cancer. Projects already approved include development of a bioreductive compound with potential as a radio and chemosensitizer, and a gene therapy approach that will convert inactive pro-drugs into toxic agents within prostate cancer cells. Over five years, fifteen new therapeutic agents for prostate cancer would be planned for development.
Rapid Access to Prevention Intervention Development (RAPID)
The RAPID program is designed to provide assistance for research and development of new agents that might be useful for cancer prevention. Under RAPID, NCI expertise and resources will be made available to the research community for the preclinical and early Phase I clinical development of potential cancer preventive agents. The program is intended to provide assistance in translating research evidence of preclinical efficacy in cancer prevention into opportunities for the demonstration of efficacy in clinical trials. This program has just been initiated; we will receive the first applications for support in November 1999.
Molecular Target-Based Drug Discovery (MTDD) Initiatives
As our knowledge of the events associated with the development and progression of prostate cancer increases, we need to shift our emphasis in the discovery, development, and testing of new agents to the molecular mechanisms that underlie neoplastic transformation, tumor growth, and metastasis. Our plan would be to use investigator-initiated grants, as well as supplements to grantees, to create an entirely new national capability for harnessing biological and technical advances for target-based discovery.
We anticipate that five new projects in MTDD could be created each year for five years, of which one or two a year would be prostate-relevant. Under these agreements, extramural scientists would develop molecular target screens of biologically relevant targets. In addition, we anticipate that up to three supplements a year could be provided to investigators to: 1) produce target molecules in sufficient amounts for use in assays to better define how to develop the compound and 2) delineate the structure of the molecular target through structure-based laboratories. We anticipate that one supplement a year would be awarded for prostate-related research.
Strategies & Plans: Specialized Programs of Research Excellence
Goals:
Expand the funded Specialized Programs of Research Excellence (SPOREs) in prostate cancer from the current three to nine or ten by 2003.
Stimulate translational research in prostate cancer by taking maximum advantage of existing research activities while continuing to expand basic research in the area.
Initiatives:
SPOREs (Specialized Programs of Research Excellence)
The NCI's challenge is to stimulate more translational research in prostate cancer by taking maximum advantage of existing research activities while continuing to expand basic research in prostate cancer. Much of this can be accomplished by proactively expanding the number of SPOREs that are dedicated to translational research in prostate cancer. SPOREs conduct research that relates to a wide range of the priority areas defined by the NCI Prostate Cancer Progress Review Group, including:
Essential infrastructure such as tissue acquisition and storage;
Development and testing of new clinical and laboratory models;
Providing scientific approaches in early detection, diagnosis, prognosis and prevention;
Development and implementation of innovative pilot and early phase therapeutic trials;
Development and testing of new technologies; and
Conducting inter-SPORE scientific studies in therapy and risk assessment that overcome traditional institutional barriers.
Currently, the NCI supports three prostate cancer SPOREs. This year, these consortia will receive support to work together to create more powerful resources for developing and testing interventions in prostate cancer. Projects we would undertake through the SPORE program include:
Consortia to develop better analytic tools for tissues primarily to provide prognostic markers for patients and identify sub-groups of prostate cancer.
Establishment of gene expression patterns in metastatic disease to look for predictors of metastasis and therapeutic targets.
Drug target development to develop new classes of drugs for the treatment of prostate cancer.
NCI anticipates the SPORE program could be expanded by six new SPOREs over the next five years. To meet this goal it would be necessary to intensively work with all of the known and developing groups in prostate cancer research to help them attain the scientific excellence necessary to compete successfully for a SPORE grant.
Centers of Excellence
Centers of Excellence consisting of multidisciplinary teams straddling the laboratory and clinical arenas would be supported by SPORE-like research grants, but would specifically focus on underlying molecular mechanisms, rather than disease. These teams would be focused on the problem of creating the essential tools necessary to do mechanism-based early clinical trials, such as clinically usable probes or assays to be used in biochemical, molecular, or imaging techniques or technologies.
The teams would likely to be composed of investigators from diverse disciplines such as synthetic chemists, radiochemists, pharmacologists, imagers, clinicians, immunologists, biologists, animal modelers, electrical engineers, and informatics experts. Within a particular mechanism-based area (e.g., apoptosis, cell cycle, signaling, angiogenesis, vaccines, etc.), the team would focus on the creation of tools appropriate to investigate their family of targets. The NCI would play a crucial role in identifying these mechanism-based areas and bringing the groups together. These Centers of Excellence would be very attractive partners for companies and potential collaborators for extramural scientists working in NCI's drug discovery process.
Strategies & Plans: Tissue Banks
Goals:
Procure and distribute well-characterized prostate tissue
Create clinical and epidemiological information links to these tissues to enable researchers to investigate effects on clinical outcomes such as morbidity and mortality
Initiatives:
Prostate Specimen Repositories
Successful development of molecular markers for detection and diagnostic markers depends on ready availability of tumor tissue specimens. NCI plans to develop a national prostate cancer tissue resource modeled on the NCI's existing Cooperative Breast Cancer Tissue Resource. NCI is considering a pilot project to test the feasibility of prospective collection and storage of frozen specimens. In addition to tumor specimens, this resource would contain clinical outcome information to allow correlation between molecular test results and cancer outcomes such as morbidity and mortality. Tissue specimens without the clinically associated information are much less useful to researchers and thus represent a key component of the repository. The collection of this information would involve careful design of the registry to provide complete protection of patient confidentiality.
Strategies & Plans: Director's Challenge for Molecular Diagnostics
Goal:
Establish the molecular profiles of premalignant changes and of prostate cancer at different stages of development for the purpose of improving tumor classification. The assortment of molecules present in cells changes during tumor development. These molecular changes provide the defining signatures of developing cancer cells. Recently developed tools for obtaining a "snapshot" of molecular changes are making it possible to identify these molecular signatures. Tumor signatures hold the promise of providing a more accurate diagnosis and prognosis for individual patients. They also should aid individualized selection of the most effective therapies and ultimately lead to the development of new therapies that target alterations in tumor cells. To ensure that this promise is realized, the NCI Director has challenged the cancer research community to demonstrate that molecular signatures can be used to improve the classification of tumors.
Initiative:
Director's Challenge
Interested investigators are currently preparing applications in response to the Director's Challenge for submission for April 1999 and November 1999 receipt dates. NCI anticipates that a substantial subset of the applications will target prostate cancer. One goal of the initiative is to make the molecular data from these studies available to the entire cancer research community as rapidly as possible.
Reissuing the Director's Challenge specifically targeting prostate cancer would increase the number of investigators working on prostate cancer and would significantly improve the prospect of making rapid progress against this difficult disease. The development of molecular profiles of prostate tumors could provide a rational basis for determining which patients with organ-confined disease need to be treated and which could benefit from watchful waiting without having to endure the debilitating side effects of surgery, radiation or chemotherapy. Better understanding of the factors that lead to prostate cancer development could result in novel strategies for prevention and control of early stage disease.
Strategies & Plans: Early Detection Markers
Goal:
Develop and validate new markers that distinguish between aggressive and indolent prostate cancers. One of the most perplexing aspects of prostate cancer is that more cancers develop in men over age 50 than ever become clinically apparent or prove lethal. Consequently, men face a serious dilemma: if their cancer goes undetected, they could develop a debilitating, potentially lethal disease; however, if their tumor would have remained quiescent for the rest of their natural life, detection could lead to the adverse consequences of unnecessary treatment. Progress in early detection requires that tests used for detection be further refined to ensure that, whenever possible, the cancers detected are those with the potential to be aggressive and effectively differentiate them from slow-growing tumors that are unlikely to cause symptoms or loss of life.
Initiative:
New Markers for Early Detection of Prostate Cancer: Early Detection Research Network
The NCI is establishing a new multi-institutional consortium to discover and develop markers that detect all prostate cancers that are aggressive and have the potential to cause symptoms or loss of life. This Network will link centers of expertise in tumor biology, diagnostics technologies, and clinical trials methodology within academia and industry to develop high-throughput assays suitable for clinical testing. The Network will have the capacity to establish estimates of the operating characteristics (sensitivity and specificity) of candidate assays as early-detection tools. NCI intends prostate cancer to be one focus of activity within the new Network. To expedite the discovery and development of more sensitive and specific markers for early disease, NCI would also establish links between activities of the Network and programs in academia and industry that are developing libraries of all known secreted proteins in mammalian cells. The goal is to develop two centers for development and early clinical testing of prostate cancer markers.
Strategies & Plans: Imaging Technology Development
Goal:
Develop imaging technologies to identify the biological properties of a pre-cancerous or cancerous cell that will aid in predicting clinical behavior.
Initiative:
Diagnostic Imaging Program
The Diagnostic Imaging Program is making a major effort to promote the discovery and development of a new generation of non-invasive imaging technologies. The goal is to have clinically usable tools that can precisely locate and biologically characterize pre-cancerous and malignant lesions. These tools will enable us to know precisely where a lesion is and how it is likely to behave. As one of NCI's Extraordinary Opportunities, imaging is receiving particular attention in NCI's planning efforts, and the benefits of vastly improved and expanded imaging approaches are likely to extend to the detection, diagnosis, treatment, and prevention of cancer. The NCI plans to embark on developing initiatives for innovative work on "smart" probes/contrast agents focused on pathways of likely significance for prostate cancer, and also plans to have initiatives for clinical trials of image-guided therapy for localized prostate cancer.
Strategies & Plans: Investigator-Initiated Research
Goal:
Maintain excellence and accelerate progress in investigator-initiated research by increasing the pool of scientists and clinicians and the number of grants funded in translational science.
Initiatives:
Research Project Grants in Translational Science
A principal support mechanism used by the NCI to foster enhanced investigator-initiated research into prostate cancer is the Research Project Grant. This mechanism permits both basic investigations into cellular and molecular questions, and research into creating interventions that translate our knowledge into improvements in treatment, prevention, and care. NCI fully expects the research community to respond with research proposals applicable to prostate cancer. NCI will pay particular attention to applications that address those aspects of prostate cancer research identified by the Prostate Cancer Progress Review Group. It is anticipated that during the course of this Five-Year Plan, approximately 215 additional investigator-initiated research grants focused on prostate cancer would be supported. Of these, approximately 60 would specifically address translational science questions in prostate cancer.
Additional Investigator-Initiated Research Grants in Prostate Cancer: Funding Grants as Exceptions to the Payline
NCI expects to use a portion of its grant funds to support high-priority applications relevant to prostate cancer. We expect to give special attention to applications that fall within the defined areas of extraordinary opportunity in the Bypass Budget but fail to meet the established payline. The NCI would give particular attention to applications addressing aspects of prostate-cancer research that are described as high-priority and important gap areas by the Prostate Cancer Progress Review Group.