This consortium has been formed with the primary purpose of defining the detailed genomic landscape of Acral Melanoma (AM) in tissue linked to an accurate and informative clinical database. We will identify new therapeutic molecular targets, validate them in xenograft models, and then rapidly translate the results into clinical trials. The unique clinical expertise in AM of the medical and surgical oncologists at both MSKCC and VICC; the large clinically annotated tumor repositories at both sites providing fresh tumor/normal paired tissue from AM patients; the Next Generation Sequencing (NGS), bioinformatics, computational and data sharing capabilities at TGen; and the plan to test clinically developed targeted inhibitors (from Novartis) for new therapeutic molecular targets identified through the genomic analysis, in AM xenografts form the key components of this proposal. A remarkable collection of tumor and normal tissue samples are stored at present in the tumor repositories of both clinical sites from a total of 52 patients with AM contributing adequate FF tumor tissue (33 MSKCC, 19 VICC). There are 12 patients with primary, metastatic, and normal tissue; 10 with primary and normal tissue, and 25 with metastatic and normal tissue, and 5 additional AM metastatic specimens from whom normal tissue is being collected. The Aims of the proposal are: 1) to integrate state-of-the-art next-generation whole genome and transcriptome sequencing of approximately 50 clinically annotated fresh- frozen samples to characterize the genomic landscape of acral melanoma; 2) to validate the presence and frequency of genetic variations of greatest interest detected in Aim 1 using over 150 clinically annotated previously banked FFPE AM samples; and 3) to test therapeutic effects of blocking the action of genes of interest, based upon results from Aims 1 and 2, using AM-bearing xenografts with agents (inhibitors) obtained from the breadth of the Novartis pharmaceutical oncology portfolio. Thereby, setting the stage to support development of clinical trials directed at the relevant genetic abnormalities found in AM. Through existing inter-institutional agreements, all tumor samples are available now for transfer to TGen for genomic analysis. TGen will perform whole genome sequencing (WGS), whole exome sequencing (WES), and RNA-seq with validation using NGS with candidate gene panel-based sequencing. Importantly, clinical annotation is available in detail for all patients for tissue used in the Aim 1 genomic analysis and Aim 2 where FFPE is available for AM tissue on >150 tumor samples present at both clinical sites. Finally, after the identification, validation, and analysis of the frequency and clinical significance of the genetic variations, we will use that information to test a large set of inhibitors in xenograft tumor models using the Novartis clinical pipeline of inhibitors with the goal of developing transformative personalized care for all patients with AM. The transfer of tumor/normal paired tissue with clinical data on site will be completed in 3 months. TGen will complete the entire genomic analysis within 12 months, including validation of the genetic variations and integration of clinical information. The next 6 months will include validation of the genetic variations in a large panel of FFPE tissue samples from AM tumors, and the final 6 months will be devoted to xenograft experiments and planning of the clinical trial. It is likely that Aims 2 and 3 will overlap for 3-4 months during the second year. This timeline is summarized in Table
|Effective start/end date||11/1/16 → 8/31/17|
- Melanoma Research Alliance Foundation (311535)
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