Cancer is a group of diseases that occur when cells become abnormal, dividing and forming more cells without control or order. For cancer to occur, a series of changes in genes that control cell growth and behavior must take place. A critical basic question in cancer research is how and why these genetic errors occur, and just as important, why the errors are not corrected by the cell's normally efficient surveillance mechanisms.
Prostate cancer research poses many of the same questions that are encountered for cancer in general; however, as with other types of cancer, prostate cancer has some unique scientific issues that must be addressed. Prostate cancer growth and development represents a continuum of biological processes, originating from early embryonic development, through growth and maturation, to aging and neoplastic transformation. To improve diagnosis, prevention, and treatment of prostate cancer, it is crucial to focus future research on the molecular, cellular, physiological, and pathogenic events that lead to uncontrolled growth and metastasis.
The foundation and engine for progress in these areas is basic, untargeted research. But while basic research studies in all areas of prostate cancer initiation, progression, and metastasis are critical, this Plan focuses on three important areas. First, we lack a real understanding of the biology of the normal prostate; our Plan would correct this. Second, our best tools for prostate cancer research are model systems - mammals, but also other organisms, cell lines, and computer simulations. Current models are inadequate for a number of reasons, but under this Plan, we would develop and disseminate the models the research community so desperately needs. Finally, NCI's Cancer Genome Anatomy Program (CGAP) is a critical component of our Prostate Cancer Plan. CGAP, whose aim is to identify genes and characterize novel biomarkers that are differentially expressed or suppressed in cancer progression and metastasis, would provide a wealth of information about the molecular and genetic contributions to prostate cancer.
Strategies & Plans: Investigator-Initiated Research
Goals:
Maintain excellence and accelerate progress in investigator-initiated research by increasing the pool of researchers and the number of grants funded in basic research and discovery.
Identify the biochemical and molecular events that govern the continuation of prostate development from early embryogenesis to adulthood
Identify the processes and determinants of all stages of prostate neoplastic growth and spread.
Initiatives:
Research Project Grants in Basic 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 80 would specifically address basic 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 pay 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.
Biology of the Prostate: From Normal Biology to Malignant Disease
The normal biology of the prostate is relatively poorly understood, and the Progress Review Group strongly recommended addressing this problem aggressively. Within the NCI portfolio of supported research there are few examples of studies on normal biology and physiology of the prostate gland. This is understandable since, by and large, the Institute funds projects and research with a focus on cancer and not on healthy, normal tissue. Lack of fundamental knowledge in the normal developmental biology of the prostate is hampering prostate researchers on many levels.
To correct the situation, the NCI, in conjunction with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute of Aging (NIA), would release a Program Announcement to invite investigator-initiated research grant applications to examine the molecular, cellular, and physiological alterations associated with the growth and development of the neoplastic, normal and aging prostate gland. The purpose of this announcement would be to encourage new projects focusing on the biology that underlies the development and progression of malignant prostatic disease (e.g., understanding metastasis of prostate cancer to lymph nodes, lung, liver and bone). Multidisciplinary collaborations among basic and clinical scientists would be encouraged.
Strategies & Plans: Animal Models
The Prostate Cancer PRG noted that many aspects of prostate research require the refinement or derivation of models and ready access to them. Ideally, if there were a single model system that encompassed all the biological aspects of human prostate cancer, from initiation through metastatic progression, the research community could apply the model to test new prevention and therapeutic strategies. However, the reality is that there currently is no single model that can address all of these needs. A variety of model systems including animals, cell lines, multi-cellular systems, and computerized simulations are needed. Research opportunities outlined below involve four strategies; the first two would be expansions of existing initiatives for mouse models, and the others would be new initiatives.
Goal:
Foster development and validation of new prostate cancer models that imitate human prostate cancer initiation, progression, and metastasis.
Initiatives:
Develop and Validate Mouse Prostate Cancer Models
Participants in the Mouse Models of Human Cancers Consortium (MMHCC) would use an assortment of new experimental tactics to generate and validate mouse prostate cancer models. To provide a focal point for the application of information about human prostate cancer to model development, we would plan to have MMHCC participants who model prostate cancer initiate a Prostate Cancer Models Forum. The Forum would have a Chairman's grant for workshops and meetings to augment the expertise of the MMHCC and to strengthen its ties to the entire prostate cancer research community. The Chairman's grant would also support the evolution of an interactive web site with the tools to accrue the knowledge for expediting prostate model derivation and validation. Based on workshops, progress in model derivation and validation in the MMHCC and elsewhere, and newly identified advances in prostate cancer research, the Forum could recommend pilot project concepts for the NCI to consider for implementation.
Develop and Validate State-of-the-Art Prostate Cancer Models in other Species
The MMHCC is designed to derive and validate state-of-the-art prostate cancer models in mice. However, to encourage additional ideas and diverse approaches for mice, as well as other animals, we would plan to fund administrative supplements for individual grants to support development and validation of prostate models in other animals in addition to mice. The supplement program may be extended to include Cancer Center core grants and SPORES.
Using Transplantation Technologies in Model Development
There is a transplantation technology whose implementation could have an immediate impact on deriving prostate cancer models. This technology became apparent when mice were developed lacking specific genes implicated in human prostate cancer, so called knock-out mice, and these mice died during embryogenesis. Verification of the function of these genes in prostate cancer will be delayed until strategies can be developed and applied. In order to further this research, we would plan to institute a research collaboration activity that consists of the three or four laboratories capable of implementing the transplantation technology research:
Rescue of the prostate gland precursor structure from late-stage embryonic-lethal knock-out embryos, and transplantation into normal male mice of the same genetic background.
Use of the "rescued" prostate glands that do develop prostate cancer to derive a resource of permanent cell lines representative of the earliest stages of prostate cancer initiation and progression.
Analysis of progressive gene expression changes from different stages (e.g., tumor development).
Creating Models to Study Prostate Epithelium and Underlying Stroma
The creation and refinement of models to study the interaction of prostate epithelium with its underlying stroma, and with endothelial, neuroendothelial, and immune cells is an important but difficult area to address. Equally challenging is derivation of models to study interaction of prostate tumor cells with the cellular components of the tissue to which prostate cancer usually metastasizes including the lymph nodes, lung, liver, and bone. NCI would plan to release a Program Announcement for phased innovative (R21/R33 and SBIR/STTR) awards to encourage development of a variety of cellular, multi-cellular, or mathematical models of normal prostate development that can be extended to understand prostate cancer etiology and progression.
The NCI has already announced administrative supplements to NCI-funded Research Project (R01) and Program Project (P01) grants to assist with unanticipated costs associated with the development and validation of mouse models of human prostate cancer. In addition, NCI-funded investigators whose research involves investigations of mouse models and who require supplemental support to take advantage of new opportunities afforded by these cancer models may submit a request detailing the basis for the needed supplement. Application submission deadlines for these supplements were April 15 and June 1.
Strategies & Plans: Cancer Genome Anatomy Project
Goal:
Identify genes and characterize novel genetically derived biomarkers that are differentially expressed or suppressed in the progression and metastasis of prostate cancer.
Initiative:
Over the past two years, the Tumor Gene Index component of the Cancer Genome Anatomy Project (CGAP) has pursued the discovery and cataloging of genes expressed during prostate cancer development. These studies, focused on normal, pre-cancerous and cancerous epithelial cells, as well as whole tumors, have resulted in the identification of over 8800 genes expressed in the prostate including 734 newly discovered genes. This progress has been remarkable and builds a platform for prostate cancer research studies ranging from prevention to early detection, to therapeutic strategies. Based on the current results, there is now an even greater opportunity to build genomic technology and information infrastructure and apply these resources in basic and clinical cancer research.