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| Yale Specialized Program of Research Excellence (SPORE) in Skin Cancer
Overall Abstract Principal Investigator(s): Ruth Halaban, Ph.D The Yale SPORE in Skin Cancer, established on July 1, 2006 by a grant from the National Cancer Institute (NCI), is a new addition to the three currently existing SPOREs in Skin Cancer. The grant, with additional funds from the Yale Cancer Center, will support translational studies on basal cell carcinoma and melanoma for the next five years. Basal and squamous cell carcinomas are the most common cancers diagnosed in the United States, and melanoma is the most devastating type of skin cancer with little effective therapy once it has spread beyond the primary site. The Yale SPORE studies include an assessment of environmental and genetic factors as they relate to early onset basal cell carcinoma, with the goals of developing methods to identify those at high risk and establishing national guidelines for prevention. The translational studies on melanoma focus on the development of prognostic and predictive blood and tissue tests to facilitate patient-tailored therapies and to monitor treatment effectiveness. Another major effort is aimed at the development of novel immunological therapies that break tumor immune-tolerance and boost patients’ immune response for eradicating melanoma cells. The Yale SPORE in Skin Cancer is a multidisciplinary program set in Yale Cancer Center that extends from the laboratory bench to cancer patients to the population. It is headed by a basic scientist, Ruth Halaban, Ph.D., and two clinicians-investigators, Mario Sznol, M.D. and Robert Tigelaar, M.D. The expertise of the SPORE investigators includes non-melanoma skin cancers, melanoma, molecular biology, genetic and genomic analysis, immunology, oncology, cancer prevention, epidemiology, bioinformatics and biostatistics. The major translational projects and co-principal investigators are: Epidemiology and Genetics of Early Onset Basal Cell Carcinoma (BCC) Temporal trends indicate that BCC incidence is increasing overall, in young adults, and especially in young women. Data from “early onset” cases support the concept that there are at least two different subgroups accounting for BCCs in individuals below the age of 40, i.e., a group with single tumors whose incidence is increasing, presumably due to environmental factors, and a group with multiple tumors whose incidence is stable and who probably have hereditary predisposition to BCCs. The purpose of this study is to assess lifestyle and genetic risk factors for early onset BCCs. In particular, we will assess the interaction between environmental factors such as artificial tanning, excessive solar radiation exposure, smoking, and obesity with genetic variants of the Melanocortin-1 Receptor gene (MC1R), known to relate to skin cancer susceptibility, or other novel genes that will be discovered through whole genome single nucleotide polymorphism (SNP) association studies. In addition, we will correlate the mutational spectrum in BCCs (frequency of UVB “signature” mutations vs. non-UVB) in a known affected gene (PTCH) with the environmental risk factors. Identification of underlying predisposition genes may help target efforts at prevention to particular genetic subgroups. Thus, this etiologic work is highly and immediately translatable into preventive interventions aimed at reducing the incidence of this exceedingly common malignancy. Predictive and Therapeutic Utilities of Epigenetic Changes in Chromatin in Melanomas Aberrant changes in gene activity due to chromatin remodeling are frequent in cancer cells. They involve methylation/demethylation of cytosine at cytosine-guanine (CpG) pair rich islands in promoter regions and post-transcriptional modifications (acetylation/methylation) of histones. Aberrant gain or loss of DNA methylation causes altered expression of genes involved in tumorigenesis and maintenance of the malignant phenotype including tumor suppressors, apoptotic factors, DNA repair enzymes, adhesion molecules, and immunomodulators. The reversible nature of epigenetic changes in chromatin is the rationale for clinical development of the DNA demethylation agents 5-Aza-2’-deoxy-cytidine (also known as decitabine), its analogue 5-azacytidine, and histone deacetylase (HDAC) inhibitors. The goal of this study is to identify epigenomic markers associated with malignant transformation that are targets for 5-azacytidine therapy currently in clinical trial at Yale Cancer Center and other institutes. These markers can be the basis for an assay for predicting efficacy and tailoring treatment with epigenetic modifiers to responsive patients. We will assess global changes in gene expression in response to decitabine in sensitive and resistant melanoma cells and determine gene-expression profiles that can predict growth suppression. We will also interrogate genome-wide changes in the patterns of DNA promoter methylation in sensitive and resistant melanoma cells in response to decitabine, and correlate it to the profiles of affected genes revealed by genome-wide gene expression analyses. The epigenetic modification (DNA methylation) in regulatory regions of specific responsive genes deemed critical to inducing growth arrest will be validated and then will be assessed in tumor specimens. We foresee that the information will help devise a cost-effective epigenetic-modifier test that can predict efficacy and monitor therapeutic responses to this class of agents in melanoma patients. Enhancement of Anti-Tumor Immunity by Inhibition of TGF-ß Signaling in Patients with Metastatic Melanoma Treatment for patients with metastatic melanoma is inadequate. A subset of metastatic melanoma patients can undergo meaningful tumor regression in response to agents that modify lymphocyte activation and/or expansion, for example, IL-2, anti-CTLA4, or IL-2 in combination with transfer of ex vivo expanded tumor-infiltrating lymphocytes (TIL). However, most patients receiving these therapies fail to respond or to achieve lasting benefit. Preclinical studies conducted in our laboratories and confirmed by other investigators provide strong evidence that inhibition of TGF-ß signaling can markedly enhance the anti-tumor activity of CD8+ cytotoxic T-lymphocytes (CTL) in animal models. This project extends these studies to determine optimal approaches for clinical development of agents that inhibit TGF-ß signaling in combination with IL-2, IL-2 + TIL, anti-CTLA4, or other related immunotherapeutic manipulations. The studies involve mouse models that are used to confirm the improved anti-tumor effects of potential inhibitors of TGF-ß and their mode of action, proof of concept clinical trials in which TGF-ß inhibition is combined with an immune-based therapy. The goal of the clinical trials is to improve the rate and quality of tumor responses in patients with metastatic melanoma and to reduce the morbidity and mortality from this disease. Serological Profiling of Melanoma Patients as a Diagnostic Tool Immune responses to autoantigens are prevalent in melanoma. Autoantibodies and tumor specific cytotoxic T-lymphocytes (CTL) have been identified, isolated and characterized. While these spontaneous immune-responses are often insufficient to induce tumor regression, they can be harnessed for diagnosis, assessing prognosis, active immunotherapy, and selection of patients for immunotherapy. A major obstacle in achieving these goals has been the variability in patients’ responses, as the experience so far is that only a fraction of patients share immune responses to the same antigens. In this project we are employing high-density protein microarrays composed of ~8,000 cloned and purified human proteins (ProtoArrays from Invitrogen) to discover novel serological responses that have not been detected by prior methods. The high-density ProtoArrays screens are performed on serum samples from patients with melanoma compared to control healthy individuals, the results are validated by other means (such as Western blotting and ELISA), and then assessed for sensitivity, accuracy and reproducibility in discriminating between sera from patients and healthy individuals, and patients with different disease stages. The results from our studies will be the basis for the development of a serum immunome-profile test for diagnosis of melanoma. The test could also be developed to assess propensity to recur, responses to therapy, and to monitor disease progression. It will enable new therapeutic, diagnostic, and prognostic options, and assist in selection of patients for adjuvant therapy and vaccine therapies. The major core facilities and co-directors are: The Specimen Resource Core The Specimen Resource Core is the center for collection, storage, archiving, and distribution of a wide spectrum of specimens. The core assembles comprehensive information on patient specimens and facilitates the development of new approaches to specimen characterization and the use of novel tools for marker diagnosis. The core maintains an integrated patient/specimen database of archived specimens with rich annotation including clinical information, pathology, family history, research allocation, and experimental results that will be integrated into the NCI tissue-banking initiative, caTissue. The two leaders of the core, Drs. Jennifer McNiff and David Rimm, ensure tight integration with Yale Dermatopathology and the Yale Cancer Center tissue microarray facility. Dr. Lisa Brailey is the core coordinator responsible for its daily activities. The Bioinformatics/Biostatistics Core The Bioinformatics/Biostatistics Core is the hub for managing and analyzing SPORE project data. A major focus is on running data management systems for tracking of biological specimens, and for processing clinical and experimental data. The goals are to integrate with existing informatics activities at Yale and beyond (such as caBIG), and to work closely with the SPORE specimen resource core. Another aim is to develop innovative tools for the analysis of genome-wide oligonucleotide and protein arrays, critical to the SPORE activities. The core directors are supported by Drs. David Tuck and Yuval Kluger (NYU) in designing and running data management systems and developing data analysis tools. The Developmental Research Projects/Career Development Program This program enhances the development of new cutaneous oncologists and scientists committed to multidisciplinary studies investigating the relevance of biological discoveries in human skin cancer risk, prevention, diagnosis, prognosis, or treatment. It also furthers the careers of individuals who have already shown interest and promise in these fields. The program currently mentors two investigators and funds four pilot projects at Yale. Contact us: Click here to learn more about: Yale Cancer Center Yale University |
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