Elizabeth A. Grimm - US grants

Use of interleukin-2 (IL-2) and IL-2 activated lymphocytes (LAK) has been proposed as a promising approach for the immunotherapy of cancer. Currently, LAK are defined functionally by the characteristics of in vitro requirement for IL-2 activation and specificity of lysis to natural-killer resistant fresh tumor cell populations. Preliminary results concerning the disease regression in patients receiving LAK therapy are inconclusive, but intriguing. Although the LAK system shares some aspects in common with that of NK and CTL, LAK are considered distinct based on a variety of characteristics including kinetics of activation, stimulus responsible for activation heterogeneous phenotype of precursor and effector cells, and specificity of lysis directed toward fresh autologous tumor cells and for modified self. While the current understanding of the LAK system is extremely primitive, extensive studies of human LAK in vitro at the precursor, activation, and target specificity areas as proposed in this project are expected to complement each other and lead to an increased understanding of the immune system as directed to cancers as well as to resolving the immunotherapeutic potential of the LAK system. LAK are generated by incubation of PBL with recombinant IL-2 (no tumor needed) for at least 3 days at 37 degrees C in standard tissue culture medium. Our first aim is to prepare monoclonal antibodies to the p75 IL-2 receptor LAKpre, in order to determine whether a unique functional cell type can be identified. Mice are immunized with LAKpre enriched PBL, and immune spleen cells fused with NS-1. And if available, the resulting MoAb will be used to purify LAKpre for application in research on the mechanism of activation and specificity of lysis. Irrespective of MoAb availability, analysis of the mechanism by which IL-2 alone appears to activate the cytolytic program of LAKpre is a second aim. We will determine minimal components needed for activation in serum free conditions; these minimal conditions will then be used to determine the effect(s) of other biologic response modifiers and cells that might be regulatory in vivo (lymphokines, regulatory lymphocytes, autochtonous tumor cell). Our third aim is to characterize the tumor cell surface component(s) responsible for susceptibility to LAK lysis. We will build on our original finding of a trypsin-sensitive site, and test the enzyme sensitivity of known proteoglycan and other glycoprotein structures in relationship to LAK sensitivity.

Lymphokine killing activity (LAK) is a form of MHC-unrestricted tumor cell killing, induced by high dose IL-2 exposure from various lymphoid populations. Although it is well established that CD16+CD56+NK cells are one major source of blood-derived LAK precursors, subpopulations of other blood and tissue-derived lymphoid cells, are also recognized as a source of MHC-unrestricted killers (for example CD3+ gammadelta+ subclasse). This LAK lytic activity, as well as the associated secondary cytokines known to be active in various inflammatory reactions (arthritis, graft rejection, multiple sclerosis, thyroiditis, and others), may be useful for immunotherapy of cancer patients. Using human PBL and designated subclasses as the source of responsive cells, this grant aims to elucidate both the direct, and indirect, responses to IL-2 with respect to secondary cytokine regulation during development of oncolytic activity. Comparisons of whole PBL and major PBL subpopulations will be used to address differential responsiveness to, and differential expression of, secondary cytokines. Specific regulation of the identified secondary factor(s) will then be explored to determine whether they are obligatory or ancillary to LAK development, suing both serologic (monoclonal antibodies) and molecular methodology (antisense oligonucleotide). We will initially focus on TNF- alpha and TNF-beta, followed by the IL-1s, IL-6, IL-7, IFN-gamma, CLMF (IL- 12)?, and later possibly others. Because a commonality of the diverse LAK precursor cell types appears to be the intermediate affinity IL-2 receptor (known as the beta chain or P70-75), our experimental plan incorporates the elucidation of cytokine regulation of p75 expression (using mAbs and Scatchard analysis) and function (LAK activation). In parallel, the cytokine-dependent expression of the IL-2 receptor alpha-chain (p55) and the TNF receptors on lymphocytes (using utr and htr mABs) will be assessed to test more fully these cytokine-mediated regulatory circuits. These studies will provide a more comprehensive understanding of the cytokine regulation, heterogeneity, and possible plasticity of the MHC unrestricted tumor killing system. Such knowledge will improve our ability to regulate the inflammatory processes during the various diseases mentioned above.

Lymphokine killing activity (LAK) is a form of MHC-unrestricted tumor cell killing, induced by high dose IL-2 exposure from various lymphoid populations. Although it is well established that CD16+CD56+NK cells are one major source of blood-derived LAK precursors, subpopulations of other blood and tissue-derived lymphoid cells, are also recognized as a source of MHC-unrestricted killers (for example CD3+ gammadelta+ subclasse). This LAK lytic activity, as well as the associated secondary cytokines known to be active in various inflammatory reactions (arthritis, graft rejection, multiple sclerosis, thyroiditis, and others), may be useful for immunotherapy of cancer patients. Using human PBL and designated subclasses as the source of responsive cells, this grant aims to elucidate both the direct, and indirect, responses to IL-2 with respect to secondary cytokine regulation during development of oncolytic activity. Comparisons of whole PBL and major PBL subpopulations will be used to address differential responsiveness to, and differential expression of, secondary cytokines. Specific regulation of the identified secondary factor(s) will then be explored to determine whether they are obligatory or ancillary to LAK development, suing both serologic (monoclonal antibodies) and molecular methodology (antisense oligonucleotide). We will initially focus on TNF- alpha and TNF-beta, followed by the IL-1s, IL-6, IL-7, IFN-gamma, CLMF (IL- 12)?, and later possibly others. Because a commonality of the diverse LAK precursor cell types appears to be the intermediate affinity IL-2 receptor (known as the beta chain or P70-75), our experimental plan incorporates the elucidation of cytokine regulation of p75 expression (using mAbs and Scatchard analysis) and function (LAK activation). In parallel, the cytokine-dependent expression of the IL-2 receptor alpha-chain (p55) and the TNF receptors on lymphocytes (using utr and htr mABs) will be assessed to test more fully these cytokine-mediated regulatory circuits. These studies will provide a more comprehensive understanding of the cytokine regulation, heterogeneity, and possible plasticity of the MHC unrestricted tumor killing system. Such knowledge will improve our ability to regulate the inflammatory processes during the various diseases mentioned above.

[unreadable] DESCRIPTION (provided by applicant): Preliminary evidence suggests that the process of melanoma tumorigenesis is promoted by aberrant constitutive production of the inducible form of nitric oxide synthase (iNOS), an enzyme responsible for production of nitric oxide (NO). The iNOS protein was first recognized as expressed by immune system cells in response to cytokine stimulation, generating muM levels of NO which directly causes the death of certain bacteria as well as local tissue damage. In contrast low (nM-pM) levels of NO production by human tumors have been proposed as responsible for increased growth, invasion, angiogenesis, genomic instability, and resistance to apoptosis as reported in leukemia, breast, colon, pancreas, and brain tumors. Our preliminary analysis of iNOS in human melanoma tumor specimens from advanced (Stage III) patients indicates that the 60% of patients whose tumors express iNOS are more likely to die within 20 months of therapy, than the 40% of patients with undetectable iNOS (p <0.0010). The functional consequences and molecular mechanisms that occur as a result of iNOS expression are critical to resolve, and are directly tested for human melanoma in the four aims of this proposal. Aim I studies the effect of iNOS levels in melanoma cell lines and whether NO levels are related to growth, vascular mimicry, invasion, or apoptosis resistance; a series of iNOS and NO inhibitors are also tested here for effectiveness in reversing the hypothesized effects. Aim II address molecular mechanisms of NO in melanoma, with an initial emphasis on the nitration of tumor suppressor proteins. Preliminary evidence suggests that a functional inactivation of wtp53 may be directly related to nitration of the p53 molecule in iNOS positive tumors. Aim III develops an in vivo model of human melanoma testing aggressiveness of regulatable iNOS in a SCID mouse model, and to apply inhibitors found in Aim I as potential therapeutic agents. Finally, Aim IV will determine if 1NOS protein presence in patient's tumors continues to predict those patients with worse prognosis. Studies of iNOS regulation and NO inhibitors may provide insight into novel therapeutic approaches, if it is found that reduction or elimination of iNOS reduces tumor growth and restores sensitivity to apoptosis and therapeutic agents. Therefore, the analysis of INOS and the functional, molecular, and prognostic consequences of iNOS expression are proposed for critical evaluation in this application.

[unreadable] DESCRIPTION (provided by applicant): Skin cancer is the most prevalent cancer in the USA, and melanoma is the most malignant of skin cancers. The incidence of melanoma in the USA is increasing more rapidly than for any other cancer. Patients with metastatic melanoma have <5% survival after 5 years, and melanoma recently replaced leukemia as responsible for more lost hours in the work place. Currently there are no approved therapies for metastatic melanoma that achieve more than a 20% response rate. The University of Texas, M.D. Anderson Cancer Center currently manages the largest number of melanoma patients in the US. Together with Callisto Pharmaceuticals Inc., which develops small-molecule anticancer drugs, we propose to explore the potential development of a recently discovered novel antimelanoma drug, WP760. WP760, is a bis-intercalating DNA binding drug which has demonstrated remarkable selectivity towards melanoma cells, based on preliminary data from the NCI in vitro anti-tumor screen. Using the Compare Program, an algorithm that compares drug profiles, researchers at the NCI found WP760 to have a highly selective activity against melanoma that was distinctly unique and different from all of the 80,000 other cancer drugs to which it was compared. In this Phase I FLAIR STTR application, we propose to further evaluate WP760's potential as a drug to treat melanoma, with the intent of moving to clinical trials in melanoma and eventual commercialization. We propose optimization of production chemistry and formulation, performance of pharmocokinetics and toxicity in rodents, sensitivity of human melanoma vs. other tumors to growth inhibition by WP760 in vitro, and finally testing of efficacy in a human melanoma xenograft mouse model using systemic administration of WP760 to approach the human use. Successful completion of these objectives will then be followed by a Phase II STTR submission for final preclinical studies, leading to an IND application and clinical trial testing in humans. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The overall goal of this University of Texas M.D. Anderson Cancer Center SPORE in Skin Cancer is to facilitate innovative research in the prevention, detection and treatment of melanoma leading to the elimination of this disease. This SPORE will achieve this goal by assembling a talented group of clinical and laboratory scientists who are committed to the translation of findings specific for melanoma from the lab to the clinic as well as from the clinic to the laboratory. The University of Texas M.D. Anderson Cancer Center has made as one of its priorities the elimination of melanomas as a health risk, and to this end, established in 1998 a Multidisciplinary Research Program in Melanoma to support training and research across traditional administrative boundaries in order to advance treatment of patients with melanoma. With this support, we have successfully organized an efficient and productive infrastructure that is the framework for this SPORE application. We are now poised to take advantage of the rapid increases in our understanding of melanoma at the molecular and cellular levels. Through this SPORE in Skin Cancer, we will enhance the translation of insights gleaned from research in melanoma biology and epidemiology to more effective prevention, detection and treatment approaches. This SPORE in Skin Cancer proposes five translational research projects, three career development positions and at least four developmental research awards all being served by three cores (Administrative; Informatics, Tissue Resource, and Pathology; and Biostatistics). The five projects address MHC-II-presented melanoma peptides engineered for optimal immunogenicity for CD4 cell activation (Project by Wang); molecular epidemiology of DNA repair enzyme function, genetics, and risk (Project by Wershenwald); evaluation of inducible nitric oxide synthase as a prognostic factor for survival and exploration of signaling cascades for therapy (Project by Grimm); regulation of IL-8 and MUC18/MCAM in combination with conventional chemotherapy as therapeutic approaches (Project by Bar-Eli); and evaluation of specific class II HLA alleles as prognostic factors for survival and evaluation of the role of associated cytokines in disease progression (Project by Lee). Through this research program and with the full support of the University of Texas, M.D. Anderson Cancer Center, we will make significant impact toward the prevention and detection of malignant melanoma processes, and treatment of patients with melanoma.

Current data suggest that the process of melanoma tumorigenesis is enhanced by aberrant constitutive expression of the inducible form of nitric oxide synthase (iNOS), an enzyme catalyzing the generation of nitric oxide (NO), normally in response to cytokines. The presence of reactive NO in melanoma is indicated by detection of nitrotyrosine (NT), which is an end-product of the chemical reaction of NO with proteins; NT formation is known to alter intracellular signaling, especially when the target is a tyrosine kinase substrate. Production of low levels (pM) of NO by human tumors is proposed to be responsible for increased angiogenesis, growth, invasion, genomic instability and resistance to apoptosis. Our analysis of human melanoma specimens from patients with advanced (Stage III) disease indicates that patients whose tumors express iNOS are more likely to die within 2 years of neoadjuvant biohemotherapy than patients without iNOS (p<0.001). Specific Aim 1 comes from the clinic to the laboratory to further test the significance of iNOS and NT in tissue specimens as prognostic markers for primary and metastatic melanoma patients. The translational goals of Specific Aim 1 are validation of iNOS and NT as new prognostic markers for survival in melanoma patients and to determine whether either marker provides independent prognostic value. Significant results will then be submitted to American Joint Commission on Cancer, Committee on Melanoma for inclusion in future staging revisions, as the first molecular marker for melanoma to be validated. Specific Aim 2 tests the hypothesis that iNOS is controlled by specific, identifiable gene transcriptional regulators including constitutively active NFKB. NFKB activation is known to regulate basal as well as cytokine-induced iNOS in normal human cells, however its role in regulation of melanoma iNOS is unknown. Specific Aim 3 builds on further upstream mechanisms of iNOS activation and tests the association and functional role of mutated B-raf, which is reported to drive MAPK independently of Ras in melanoma cells. A novel molecular heteroduplex analysis will be employed to detect mutated B-raf in paraffin-embedded tumor specimens, and study of its association with iNOS and constitutive NFKappaB. The regulation of mutated B-raf activity is also proposed in Specific Aim 4 as a means to regulate iNOS and, by extension, melanoma growth.

The overall aim of the Melanoma SPORE Developmental Research Program is to support promising pilot translational studies in melanoma, particularly those projects that will generate clinically testable hypotheses aimed at reducing the incidence or mortality rate or improving the quality of life of patients with melanoma. Proposals for innovative translational research will be solicited by the SPORE Executive Committee of the Administrative Core by announcements to all institutions in the Houston Medical Center. The Executive Committee members will help investigators submitting proposals to formulate their translational specific aims and research plans, as many of these investigators may not have expertise in this area. The process will therefore be a major educational activity to further stimulate the development of innovative translational research concepts in melanoma. Proposals will be screened first for appropriate SPORE qualifications by the Executive Committee by using objective criteria of melanoma research focus and justification of budget. Proposals will then be forwarded to members of the External Scientific Advisory Board (EAB). On the basis of the scores received from the EAB, the final selection of the research projects for funding will be made. The projects will be funded for at least one year, beginning in year one of this SPORE; extensions may be awarded for an additional year based on progress and need. As part of our continuing efforts to expand melanoma research at M.D. Anderson Cancer Center, an institution-wide announcement and solicitation for pilot projects was made in the summer of 2002; after elimination of projects considered to be purely basic science and several considered to lack sufficient merit for further review, 8 were determined to be consistent with the translational focus of the SPORE. These 8 proposals are included within, and are representative of those that will be reviewed for funding consideration this year, and funding of 4 is predicted. These 8 projects illustrate the breadth and depth of interest in melanoma translational research at our institution.

data management; melanoma; biomedical facility; statistics /biometry; experimental designs; mathematical model; computer simulation;

The goal of the Melanoma SPORE Career Development Program is to develop an integrated cadre of investigators at all levels of training dedicated to translational research on human melanoma. The program will (1) recruit junior and senior physicians and basic scientists and support them to become competent translational investigators in the study of malignant melanoma, (2) provide in-depth training in basic science principles of cancer biology that are not commonly included in clinical fellowship training or Ph.D. programs, and (3) teach the fundamentals of the specific biology and clinical course of human melanoma to improve the ability of the awardees to conduct innovative translational research on this disease. The unique educational environment at M. D. Anderson and in the M. D. Anderson Melanoma Multidisciplinary Research Program will assure that these goals will be met. Three career development trainees (prefer 2 faculty and 1 fellow) will be supported annually. Solicitations will be made yearly for qualified candidates from within and outside of M. D. Anderson. The awardees will be reviewed and ranked by the SPORE Executive Committee and Internal Advisory Committee, with final decision made by the External Advisory Committee Renewals. Second years of support will also be contingent upon review by the Internal Advisory Committee. Our mentorship program includes nationally recognized clinical and laboratory translational investigators who will provide comprehensive training. The mentors have been selected from a diverse group of scientists and clinicians based on their interest in translational melanoma research and skill as educators, includes all senior SPORE faculty at Associate Professor or higher. The program will be evaluated annually, and the selection and training processes will be modified as required. Career Development will be maintained through out the term of the SPORE.

The goal of the SPORE Development Research Program is to promote new ideas directed toward the SPORE translational melanoma research. SPORE guidelines mandate diligent efforts to identify and fund pilot projects by providing a formal Developmental Research Program (DRP) that will highlight and support new research endeavors, whether collaborative among scientists within one or more SPOREs, or with new scientists outside the SPORE environment, that may eventually reduce the incidence and morbidity or increase the survival of melanoma patients. Both laboratory and clinical research projects are eligible for funding although the projects must aim toward a translational goal. A portion of the NCI SPORE budget ($75,000 per year) will be allocated annually to support these pilot projects. With matching funds (an additional $100,000 per year for each the DRP and CDP) provided by the M.D. Anderson as part of its nstitutional commitment to the SPORE, we have had $175,000 each year to support the DRP in Melanoma. Over these 4.5 years the SPORE DRP has supported 36 DRP in melanoma awards. The number of awards offered each year varied, depending on funds, based in large part on the actual balance due to whether previously funded projects were approved for a second year of funding. Our results, show that SPORE funds greatly enhanced and expanded the potential for development of new projects in which preliminary data was required before the project could move to a full SPORE project, or compete for other funding. We have achieved the specific objectives of the DRP. The 36 different projects funded to date represent investigators from 16 different Departments and Divisions at M.D. Anderson as well as at our neighboring institutions, including the U.T. Medical Branch at Galveston. Although our SPORE is young, and the early awardees just now are seeing the results of their funding, this effort has led to significant progress including 4 DRP investigators now included as Co-Leaders of full projects, 43 manuscripts submitted, and/or published. Twenty-one grants were submitted with 14 of these receiving funding and 4 under review at this time. These advances are evidence of the importance and success of the SPORE Developmental Research Program to melanoma research overall as well as to our local efforts at M.D. Anderson. Our plans are to continue this program by solicitation of proposals for a maximum of $50,000 each, and provide the initial installment of $25,000 followed by an additional $25,000 if the initial goals are met and the progress and need can be justified to the Executive and lAB committees.

PROJECT SUMMARY (See instructions): In our 2004-2009 SPORE, we, studied the prognosfic significance of iriducible nitric oxide synthase (NOS) protein levels in both primary and metastatic melanoma, as well as the geneficand pharmacologic regulafion of its constitutive expression. The results confirmed that iNOS protein is readily detectable in melanoma cell cytoplasm in the majority of patients, and the quanfity, as detected by immunohistochemistry (IHC), provides prognostic information by identifying piatients with poor survival in bPth univariate and mulfivariate analysis (p<0.001), independently of AJCC staging and associated prognosfic criteria. Melanomas are recognized to be heterogeneous based on efiology and somafic mutafional status and have aberrant expression of inflammatory genes and proteins. We aim to expand the tesfing of INOS protein expression as a clinically useful prognosfic marker and propose that INOS repi^esents a "node" of an identifiable melanoma inflammatory and oxidafive stress network. We further hypothesize that a "signature of poor prognosis" for melanoma can be gerieratedby directly tesfing tumors for expression of INOS-related inflammatory markers. Testing for associafion of iNOS protein expression and levels with both geriefic alterations (mutations of BRAF and A/RAS) arid mitogen-activated protein kinase (MAPK) pathway acfivafion was also performed in a large series of primary cutaneous tumor biopsies. We report that acfive MAPK can drive iNOS expression and that inhibition of MAPK arid/or 6/?AF inhibits INOS protein expression. iNOS protein in melanoma was also found to be sensifive to down regulation by pharmacologic agents, possibly fpr therapeutic advantage. Pharmacologic inhibifion of INOS or inhibifion of its product, nitric oxide (NO), restores chemosensitivity in iNOS-posifive melanoma cell lines. Building on these results, three new specific aims are now proposed: 1) identify iNOS-related inflammatory nnarker genes expressed in melanoma, as part of a proposed signature 2) determine which candidate marker proteins can be identified in melanoma tumors by standard immunohistochemistry and whether their presence iadds value to the INOS survival prediction model, and 3) test the inflammatory stress pathway as a target for melanonia patient therapy in a Phase l/ll trial using an anti-inflarnmatory drug that inhibits expression of INOS and other inflammatory mediators.

DESCRIPTION (provided by applicant): The overall goal of this competing renewal SPORE in skin Cancer from The University of Texas M.D. Anderson Cancer Center is to facilitate innovative translational research in the prevention, detection and treatment of melanoma leading to the elimination of the disease. This SPORE aims to achieve this goal by assembling a talented group of scientists who are committed to the translation of melanoma-specific findings from the laboratory to the clinic as well as from the clinic to the laboratory. The University of Texas M.D. Anderson Cancer Center has prioritized the elimination of melanoma as a health risk, and to this end established in 1998, a Multidisciplinary Research Program in Melanoma to support training and research across traditional administrative boundaries. The program provided resources and a structure that led to our successful funding in 2004 for the first SPORE dedicated entirely to Melanoma, which allowed us to further advance along several translational themes and provide a basis for this renewal application. This SPORE in Melanoma proposes five translational projects, four of which included treatment protocols to begin in successive years and takes advantage of our large melanoma patient population. The five projects and four protocols are served by three cores: Administrative (A), Informatics, Tissue Resource, and Pathology (B), and Biostatics and Bioinformatics (C). The Developmental Research Program (DRP) and Career Development Program (CDP) continue as successful aspects of our SPORE as each new project incorporates at least one DRP/CDP awardee as a new Co-Leader. The five proposed projects address activation of Toll-Like Receptors (TLR) for specific immune stimulation (#1); inhibition of pSTAT3 for control of melanoma metastasis focused in the CNS (#2); elucidation of melanoma JNOS-related inflammation for development of a prognostic signature as well as a target therapy (#3); systemic deliver of angiogenesis inhibitors using nanoliposomal technology (#4); and genetic mechanisms of immunity and inflammation to generate an integrated risk model as part of a population based project (#5). Through this research program and with the full support of The University of Texas M.D. Anderson Cancer Center, this SPORE aims to make a significant impact toward the prevention, detection, and treatment of melanoma in patients.

The goal pf the Melanoma SPORE Career Development Program (CDP) is to develop an integrated cadre of investigators at all levels of training dedicated to translational research on human melanoma. We have successfully accomplished this goal over the past 4.5 years of this SPORE through our funding and training of ten CDP recipients who are now supporting their melanoma research through 1 R01,1 CIDR, 2 R21s, and one MDACC Institutional grant on melanoma. In addition they have generated a substantial quantity of new data and information resulting in 20 publications. We will continue this program and aim to (1) recruit junior and senior physicians and basic laboratory scientists and support them to become competent translational investigators in the study of melanoma, (2) provide in-depth training in translational science principles of human cancer biology not commonly included in clinical fellowship training or Ph.D. programs, and (3) teach the fundamentals of the biology and clinical course of human melanoma to improve the ability of the awardees to conduct innovative translational research. The unique educational environment at M.D. Anderson and in the M.D. Anderson Melanoma Multidisciplinary Research Program has and will continue to assure that these goals are met. Up to three career development trainees (preferably 2 faculty members and 1 post doctoral fellow) will be supported annually. A portion of the NCl SPORE budget ($75,000 per year) plus half of the institutional commitment funds ($100,000 for the CDP per year) provided by the M.D. Anderson is available to the SPORE, resulting in $175,000 each year to Support the CDP in Melanoma. Solicitations will be made yeariy for qualified candidates from within and outside of M.D. Anderson. The awardees will be reviewed and ranked by the SPORE Executive Committee and Internal Advisory Committee, with final decision made by the External Advisory Committee. A second year of support will also be available contingent upon review by the Internal Advisory Committee. Our mentorship program includes nationally recognized clinical and translational investigators who provide comprehensive training. Their success is evident in the accomplishments of the group of scientists awarded CDP awards over the last 4.5 year. Two of these individuals are now full contributors of this SPORE serving as Co-Leaders of projects. We propose to continue the high standards we have established and evaluate our program annually. We will modify our selection and training processes as required allowing us to continue to train future scientist in translational research on human melanoma throughout the term of this SPORE.

The Administrative Planning and Evaluation Core, Core A, is critical to the success of the SPORE. Dr. Elizabeth Grimm is the overall Core Director, and is assisted by three Co-Directors, including the founding Co-Director, Dr. Jeffrey E. Lee, who will chair the Executive Committee meetings which will be composed of all Co-PIs and one leader from each Project and Core. Two new co-directors include Patrick Hwu, M.D., as director of the Clinical Trials Resource which for now will be incorporated as part of Core A;and Jeffrey E. Gershenwald, M.D., as overall director of patient informatics and tumor acquisition and distribution. Our Executive Committee will meet monthly to review scientific progress and fiscal status and will help surmount problems or barriers to assure that all goals are met within a realistic timeframe and within the budget constraints. This Administrative Core will schedule all meetings with investigators and assure optimum communication with investigators at M.D. Anderson Cancer Center and elsewhere. All SPORE investigators will participate in weekly melanoma seminars and regulariy report progress to the Internal Advisory Committee. An External Advisory Committee will evaluate status and progress of all SPORE research programs by annual meetings either in Houston or by web/video or teleconference. Specific responsibilities of Core A include * Compliance with all general, governmental and NCI regulations and requirements. * Communication and consultation with the NCI in preparation of all required reports and publications. * Coordination of data control quality assurance issues * Oversight and support for the Informatics, Tissue Resource and Pathology Core B. * Optimization of clinical trial efforts by a Clinical Trials Management Resource in this Core A. * Maintenance of fiscal and budgetary functions, and managing flexibility in funding. * Convene SPORE Administrative meetings, including the Executive Committee, the Internal and External Advisory Committees, weekly scientific meetings, quarteriy research meetings, lectures, and symposia. * Administration of the Developmental Research and Career Development Programs. * Coordination and Funding of Patient Advocate activities. * Establishment and monitoring of policies for recruitment of women and minorities of this program. * Coordination with other SPORE sites to promote and maintain communication and integration through sponsoring and/or attending a yeariy Skin SPORE conference, and also through sharing and distribution of materials, electronic communications, and evaluation of progress reports.

Career Enhancement Program: Project Summary/Abstract The goal of the Career Enhancement Program (CEP) is to use the translational research resources at the MD Anderson Cancer Center (MDACC) to solicit and award faculty-level investigators interested in intensive career development in the field of melanoma research to improve melanoma early detection, prevention, and treatment. Experienced mentors serve to assist CEP awardees to develop their careers as melanoma experts, with the goal to reduce the morbidity and mortality from this disease. The CEP will support up to three one-year awards of $50,000 annually, with a second-year renewal based on acceptable progress. Funds for the CEP include an annual $50,000 from the SPORE throughout the duration of the overall award, as well as up to $100,000 per year in institutional ?matching funds? from MDACC. Candidates will include the most promising faculty-level investigators from our institution as well as from the entire Texas Medical Center, and other SPOREs, with which we interact. The selection of CEP awardees will be based on the scientific uniqueness, quality, and novelty of the research proposal and the appropriateness of the mentoring plan, which will be evaluated and scored by our Internal and External Advisory Boards (IAB; EAB). The awardees will meet with their designated mentors regularly and with CEP leadership at least monthly, and are expected to participate in and report their progress at monthly SPORE investigator meetings and annual IAB/EAB meetings. The CEP is led by Dr. Elizabeth Grimm for mentees with laboratory-based projects and Dr. Jeffrey E. Lee for mentees with clinical projects; both will be involved to mentor translational researchers.