Within the Melanoma Biomarker Group Collaboration, Dr. Hoon's lab will undertake an unbiased, genome-wide survey of melanoma in an effort to create structural and functional "melanoma signatures". Importantly, this effort will create the highest achievable resolution "maps" of these features and integrate DNA copy number, LOH, epigenetic changes, and gene expression patterns into one unified database, and mapped back to their physical location within the genome. His group will also derive a set of cloned cell lines from cryopreserved single cell suspensions and generate at least 30 cell lines derived from patients with Stage III melanoma with known clinicopathology and long-term follow-up. They will be expanded for many purposes, including preparation of Tissue Microarrays and for additional molecular characterization such as redox markers by Dr. Grimm. Dr. Fisher will take five of the melanoma cell lines selected by the Group and use RNAi based knockdown of all known drug-able genes to identify pathway(s) and small molecules of preclinical importance. These lines will also be subjected to a combinatorial 2-drug screen employing 10,000 drug combinations with approved, available drugs for which efficacious pairings can be both mechanistically and preclinically pursued.
These studies will rapidly identify previously hidden vulnerabilities of melanoma cells, and are designed to be translated into clinical trials. In parallel, Dr. Herlyn will use the freshly thawed tumor cell suspensions to study stem cells. Sensitivity to signaling pathway inhibitors will determine whether stem cells respond differently to signaling inhibitors than the main population of tumor cells. Dr. Witz's component of the collaboration involves the establishment of a chemokine and chemokine receptor profile of melanoma brain metastases. The central hypothesis to be tested is that melanoma brain metastases are driven by interactions between chemokine ligands expressed in the brain or on brain endothelial cells and chemokine receptors expressed by brain seeking melanoma cells. A melanoma brain metastasis panel of tissues and cell lines will be created as a renewable resource using material from the John Wayne Cancer Institute. The objective is to identify novel chemokine receptor-ligand axis biomarkers and drug targets for the treatment of brain metastasis.
The aim of the Melanoma Adoptive Cell Transfer Collaboration is to make available the adoptive cellular transfer technology originally developed at the Surgery Branch at the National Cancer Institute to four other institutions through a multi-institutional protocol using preparative chemotherapy and cultured T-cell infusion with IL-2 in patients with melanoma. The objective is to determine if the dramatic initial results seen at the NCI can be confirmed by others and if additional measures can improve upon the original protocol. The selected institutions are the John Wayne Cancer Institute, M.D. Anderson Cancer Center, the H. Lee Moffitt Cancer Center and the Hadassah Medical Organization. The basic adoptive cell transfer approach will provide each of the participating institutions a vehicle for advancing and translating their particular area of expertise so that all groups can benefit by rapidly adopting successful modifications. In addition, several initiatives, based on promising pre-clinical studies, are being pursued by the Surgery Branch, exploiting their expertise and extensive experience in the gene therapy of lymphocytes. These efforts have the following aims; 1) expanding patient eligibility to those whose lymphocytes (TIL) cannot be grown, 2) simplifying procedures by using only patient blood and off-the-shelf reagents to make cells for transfer and 3) improving overall efficacy by constructing cells with consistently better tumor recognition.