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The Johns Hopkins University School of Medicine
The Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancer at the Johns Hopkins Medical Institutions supports a highly interactive, multidisciplinary, and inter-institutional program. Eight research projects within four research programs, four cores, a career development and a research developmental program are tightly interwoven to further translational research in colorectal and pancreatic cancer. Project 1A Over the past two decades, the molecular genetic analyses of human cancers have led to unprecedented insights into these diseases. This is especially apparent in human colorectal cancers where a series of somatic mutations that drive the process has been delineated, the genetic bases of several inherited predispositions to cancer have been defined, and detailed expression analyses have identified a myriad of expression changes associated with neoplastic growth. The goals of this project are to apply this new knowledge to the improved management of human colorectal cancer. The aims of this project can be divided into efforts designed to use somatic mutations, germline mutations, and gene expression analyses to improve early detection, prevention and management of human colorectal tumors. Recent advances from this project include the identification of cancer mutations in most patients through use of a noninvasive stool assay developed by our SPORE. Project 1B During the past seven years of this SPORE project, we were first to identify in pancreatic cancer the nearly ubiquitous inactivation of the p16 gene, and the genetic inactivation of BRCA2, TGFb receptors I and II, activin receptor IB, LKB1/STK11 (Peutz-Jeghers), DPC4/SMAD4, mitochondrial genome, DCC, and mismatch repair genes including MLH1. We confirmed the mutations of MKK4 and identified a distinctive nature of K-ras wildtype tumors. The discoveries provided insights into tumor biology, familial aggregation, and histologic tumor classification now applied in clinical practice.Our long-term goal is to identify the metabolic and regulatory pathways that are altered reproducibly in pancreatic tumorigenesis in order to construct a general theory that explains tumor behavior, provides improved epidemiologic and diagnostic tools, and enables rational therapy. In the proposed grant period, we will acquire essential knowledge to advance this goal through identification of mutant genes, other genomic alterations, and the clinical relevance of these patterns. Project 2A Pancreatic carcinoma usually presents at an incurable stage. The precursor is the pancreatic intraepithelial neoplasm (PanIN), occurring in up to 60% of the older population. Only a small subset is histologically advanced and progresses to invasive cancer. Invasion induces an exuberant host:tumor interaction that remains poorly understood, but is likely to have fundament influences on tumor biology and distant host organs. Therefore, pancreatic carcinogenesis is now understood as a progression of intraepithelial neoplasia and as an interaction of cellular compartments. During the past seven years of this SPORE project, we defined a progression of alterations in the K-ras, p16, DPC4/SMAD4, Her2/neu, and BRCA2 genes in the precursor lesions. Variant tumor types were re-interpreted within this tumorigenic model and we comprehensively profiled gene expression through SAGE analysis. A progression model of neoplasia was constructed, contributing to a new consensus classification system for PanIN lesions. Our long-term goal is to identify the fundamental genetic alterations and patterns of gene expression in the progression of precursor lesions to invasive carcinoma, in order to guide diagnosis and therapy. Recent advances from our group have included markers of pancreatic cancer that are not present in normal tissues and an examination of the communication between tumors and neighboring patient tissues, leading to new putative diagnostic and therapeutic targets. Project 2B Pancreatic cancer is the fifth leading cause of cancer death in the USA. Unfortunately, there is currently no effective screening test for asymptomatic disease and the vast majority of patients with pancreatic cancer present with advanced incurable disease. Most early pancreatic cancers are too small to be detected using standard imaging techniques such as CAT scan. However, it may be possible to detect the presence of early pancreatic cancer by analyzing blood, stool, or pancreatic juice for the presence of molecular alterations that arise in the pancreatic cancer that are not found in normal pancreas. Such molecular alterations include DNA alterations, such as abnormal methylation of DNA or DNA mutations, or the presence of proteins not normally found in the pancreas. With this in mind, we are working to identify and characterize a panel of markers for early detection strategies, to test these markers in the biologic fluids of patients with pancreatic cancer and to determine when such markers become manifest during pancreatic neoplastic development. Project 3A Colorectal cancer is the second leading cause of cancer deaths and is also among the most highly preventable forms of cancer. Screening for the detection and removal of precancerous conditions is effective, although somewhat onerous. In view of this, a critical step in the prevention of colorectal cancer is the identification of individuals at high risk of developing the disease. A natural subgroup to target are individuals who are at high risk because of their family history. Recent progress in molecular biology has led to the identification of colorectal cancer susceptibility genes known as HNPCC genes. The chance of carrying a genetic mutation of one of these genes varies markedly from individual to individual, depending in complex ways on family history of colon and related cancers. As a result, increasing attention needs to be given to understanding and conveying risk information in an individualized way. We are working to develop and validate a methodology for accurately assessing the probability that an individual carries an inherited genetic susceptibility to colorectal cancer, based on his/her family history. Such a model would find wide and direct clinical applicability in counseling families interested in testing, and in identifying individuals for targeted preventative interventions. Project 3B Pancreatic cancer is an almost uniformly fatal disease that will strike ~29,000 families in the United States this year. It has been estimated that 5-10% of these cancers have a familial basis. A better understanding of the genetic basis for the familial aggregation of pancreatic cancer will form a foundation for counseling patients and their families, and a basis for the rational application of new tests to detect this disease earlier. This project builds on progress made during the last funding period of this GI SPORE in which we demonstrated that germline mutations in the BRCA2, STK11/LKB1, hMLH1 and p16 genes are associated with an increased risk of developing pancreatic cancer; in which our segregation analysis of 273 pancreatic cancer cases and their families supported the involvement of a major gene in the familial aggregation of pancreatic cancer; and in which we prospectively demonstrated a significantly increased risk (18-fold, 95% CI 4.7-44.3) of pancreatic cancer in first-degree relatives of patients with familial pancreatic cancer. We will continue to determine the patterns of inheritance of pancreatic cancer and other cancers in such families. Project 4A Over the past two decades, unprecedented advances have been made in delineating the underlying molecular mechanisms of tumorigenesis. However, the sobering fact is that the tremendous advances made in understanding the molecular details of cancer have so far failed to result in corresponding reductions in the mortality rates of the most common epithelial cancers. The goal of this project is to use emerging molecular genetic insights from colorectal cancer to devise new strategies for rational preventive intervention to block tumorigenesis. Chemoprevention is a pharmacological approach to arresting or reversing the process of tumorigenesis early, during cancers' typically prolonged latent period (often 20 years or more in humans). Three key components lead to new rational preventive approaches: 1) defining molecular pathways is a crucial step in choosing targets for new chemopreventive strategies, 2) mouse models genetically engineered to develop precancerous lesions with genetic alterations relevant to the initiation or early progression of the corresponding human cancer are a powerful tool to characterize lead strategies in vivo, 3) clinical evaluation of promising leads provides insights with the necessary direct relevance to human cancer. Current colorectal chemopreventive regimens employing NSAID's are not completely effective in preventing tumors and are associated with adverse side effects. In work supported by the SPORE, we have already developed a novel combinatorial chemopreventive strategy using a class of compounds represented by EKB-569, a potent irreversible inhibitor of epidermal growth factor receptor kinase. A combination of EKB-569 and low dose sulindac was remarkably effective in the chemoprevention of mouse intestinal tumors. In the proposed studies we will use the combination of tools outlined above as the engine for translation of emerging knowledge of the molecular pathways involved in colorectal cancer into improved chemoprevention strategies. Project 4B Pancreatic adenocarcinoma continues to be one of the most difficult cancers to treat; new therapies are urgently needed. Murine studies employing tumor cells genetically-modified to express cytokines have demonstrated the induction of potent T cell immunity that can cure mice of pre-established tumors. Although the specificity of the immune response seen in these models suggests that antigens expressed by the tumor are recognized by the ensuing immune response, in most cases the identity of these antigens is unknown. The recent sequencing of the human genome provides a unique opportunity to more rapidly identify candidate pancreatic cancer antigens. Taking advantage of new RNA expression technologies like SAGE, our gene discovery colleagues in the SPORE program are rapidly developing a database of proteins that are differentially expressed by pancreatic tumors. Drawing on our previous experience with antigen identification, and utilizing materials from patients concurrently enrolled on a vaccine study, we can identify tumor antigens expressed by human pancreatic adenocarcinomas. Candidate antigens that are identified are further analyzed for recognition by pancreatic cancer-specific T clones that we generated and for the ability to stimulate naïve T cells. Ultimately, the identification of common pancreatic antigens will allow the development of generalized vaccine approaches that can induce immune responses potent enough to treat pancreatic adenocarcinoma. Core 1 This core is responsible for managing the SPORE and disseminating information within the SPORE and for external interactions. The Core is designed for low-cost, yet efficient administration and communication in order to focus funds on research activities. Core 2 The purpose of this shared resource is to provide human tissues, biological fluids, and expert pathologic interpretation for investigators on all of the projects under the direction of expert pathologists. The Histopathology and Tissue/Biologic Fluids Resource has been in existence since 1986 and expanded under the support of the GI SPORE. Specimens are collected under the supervision of pathologists with expertise in colorectal and pancreatic neoplasia in close collaboration with clinical specialists in these areas and in similarly close collaboration with basic research investigators to maximize translational impact of the projects. Core 3 A registry and clinical study of patients with hereditary polyposis and colorectal cancer syndromes were developed at the Johns Hopkins Hospital in 1973. Nine years later the Bowel Tumor Working Group was formed to study the pathobiology and molecular genetics of colorectal tumors. The Registry includes: 1) family histories and food frequency questionnaires on patients evaluated for colorectal neoplasm and 2) families with a history of familial aggregation of colorectal cancer and early onset colorectal cancer and polyposis syndromes. The CORE was expanded in 1996 to collect similar data from pancreatic cancer patients. Currently, the CORE for Colorectal and Pancreatic Cancer collects family history, medical history, environmental/exposure data, and dietary data from affected and at-risk individuals and procures specimens from identified individuals to support investigation of familial and environmental factors and molecular genetic alterations in both colorectal and pancreatic cancer. Core 4 The primary purpose of the biostatistics core resource is to provide technical support in study design, data management, study conduct, data analysis and interpretation, and scientific report writing for all projects in the SPORE. All of the investigators in the proposed GI SPORE Biostatistics Core resource have history of collaboration with the investigators of the various SPORE projects, and have a good understanding both the biologic and analytic questions and challenges. Developmental Projects Program The Developmental Research Program is a major focus of the SPORE because it provides for a continuous flow of innovative ideas and activity to stimulate investigation in the context of SPORE translational research. The Program provides a means to respond to new opportunities, and is designed to encourage and facilitate new research efforts. The Program takes advantage of the broad expertise of researchers at The Johns Hopkins University and of external investigators by providing funds for pilot projects with potential for development into full-fledged translational research avenues, collaborations, and new methodologies for integration into other Research Projects. Career Development Program The emphasis of the Career Development Program is on recruitment of young or established investigators from the talented pool throughout the institution to direct their research career focus upon translational progress in colorectal and pancreatic cancer. This Program provides multi-year support for research expenses during the critical early period of their careers. |
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