Executive Summary The applicant proposes to establish a mutidiscpinary and multi-institutional team of basic and clinical scientists for a basic and translation study on melanoma cancer stem cells. Melanoma is the leading cause of death due to skin cancer. Recent research implicates cancer stem cells in the origin, progression and relapse of malignant disease. Targeting these stem cells may be necessary for the eradication of metastatic cancer. The proposal aims at optimizing the isolation and characterization of genetic and epigenetic changes as well as biochemical and cell biology properties associated with melanoma cancer stem cells. Identification of target genes and pathways characteristic of melanoma stem cells may lead to development of new modalities for diagnosis and therapy of metastatic melanoma. There was general agreement among the reviewers that the scientific rationale and approach are appropriate for this clinically significant problem. However, the focus of the scientific aims is on basic concepts, and the translational aspects need to be targeted more specifically. The proposal describes an approach to identify possible targets on melanoma stem cells but the plan of attack for bringing to the clinic is not well-developed. The proposed team includes a large number of experts in the basic, translation and clinical research. The Prinicipal Investigator (PI) has a long track record in melanoma biology with publications in reputable journals. Reviewers found the organization and plans for developing the disease team proposal to be a major limitation. The structure of the collabrative efforts are not clearly defined. Thus, although the concept is scientifically appropriate, the design and layout of this disease planning team is poorly constructed. Overall enthusiasm for the proposal was diminished. Reviewer Synopsis Melanoma is one of the most aggressive human cancers. Melanoma with distant metastases has a terrible prognosis with median survival of 6-9 months. This disease planning proposal will generate additional knowledge regarding melanoma cancers through analysis of melanoma stem cells including their isolation and characterization of genetic and epigenetic changes as well as biochemical and cell biological properties. This extensive characterization will involve an outstanding team of experts in melanoma biology and will be expected to result in discoveries with profound implications for the development of therapies focused directly on molecular engines driving melanoma stem cells. These studies will provide a great opportunity to translate basic stem cell science into clinical advances. The program will rely on cooperation among leading scientists in the field of melanoma and stem cell biology that will keen up to enable comprehensive, characterization and assessment of known means for diagnostic and therapy. Reviewer One Comments The applicant presents a good rationale for studying melanoma stem cells, and the PI appears to be qualified to lead this effort. Overall this is a large but appropriate approach to study the biology of melanoma and will amass a collection of California melanoma and stem cell biologists as well as external experts. Almost a dozen phases of this disease planning grant will have assigned local and collaborative cell biologists and clinicians as outlined in the team approach. Major limitations of this proposal are that the proposal lacks description of a plan to approach the development of the team in terms of how this team will get together, what meetings will be convened, how individuals will be brought together, and how the funds will be used to energize and begin the planning stages of a team grant. Thus, the concept and target are fantastic but the design and layout of this disease planning team, is poorly constructed. Reviewer Two Comments Concept: The concept, as well as the approach toward resolution of the problem, is innovative but challenging, as melanomas are very small (4mm max) but devastating tumors. To address a possible role of cancer stem cells in melanoma formation is therefore highly significant. The proposal aims at optimizing the isolation and characterization of genetic and epigenetic changes as well as biochemical and cell biology properties associated with melanoma cells. Principal Investigator: The PI has a decent but not spectacular track record of publications, and is certainly capable of undertaking the aims. How this will be coordinated remains poorly described. However, the stem cell environment at the Burnham remains among the best in California. Planning Approach: Specific aims include the identification of target genes and pathways that are characteristic of melanoma stem cells, which can be used as new modalities for diagnosis of metastatic melanoma. The approach is scientifically sound and well developed. Two consultants and collaborators are included and would provide specific expertise as required. While the science is sound and significant, their plan of attack is not well developed and the structure of the collaborative efforts remains poorly defined. A total of 11 specific aims are listed as follows: (i) isolation and characterization of melanoma stem cells (Alexey Terskikh, BIMR, with Meenhard Herlyn as consultant from the Wistar Institute) (ii) identifying genetic changes in melanoma stem cells (Boris Bastian, UCSF); (iii) signaling pathways in melanoma stem cells (Ze’ev Ronai, BIMR, with David Fisher as consultant from Harvard University); (iv) receptors in melanoma stem cells (Elena Pascuale, BIMR); (v) motility / migration of melanoma stem cells (Sara Courtneidge, BIMR); (vi) ubiquitin ligases in melanoma stem cells (Dieter Wolf, BIMR); (vii) metabolomics of melanoma stem cells (Andrei Osterman and Jeff Smith, BIMR), (viii) proteases and apoptotic pathways in melanoma stem cells (Guy Salvesen, BIMR); (ix) mouse models for melanoma stem cells (Martin McMahon, UCSF); (x) drug discovery using structure based design for targets identified by the co-leaders of this program (Maurizio Pellecchia, BIMR). (xi) Clinical evaluation, diagnostic and therapy of metastatic melanoma (Adil Daud, UCSF). Overall, these aims represent good and solid basic science, but the translational aspect of the work needs to be targeted in a more specific fashion. Reviewer Three Comments Concept: Melanoma is the leading cause of death due to skin cancer. Recent evidence suggests that melanoma may be a disorder of stem cells, with populations isolated from melanoma which have t otipotent features, ability to repopulate tumors from small inocula, and expression of stem cell markers. These include NGF p75 and ABCB5. Targeting these stem cells may be necessary for eradication of metastatic melanoma Principal Investigator: Dr Ronai has a long track record in melanoma biology, with publications in the Journal of Clinical Investigation, Cell, and PNAS. Among his accomplilshments are elucidating the role of the transcription factor ATF2 in melanoma. Planning Approach: The PI has assmebled a large group of melanoma experts, mostly from California, but some outside of California. This group would benefit from the inclusion of Dr Lynda Chin of Harvard. Otherwise, it has many of the experts in melanoma signaling, and is well suited to determine the phenotype of the melanoma stem cell.