Precision Medicine by Targeting Cell Adhesion in Melanoma

项目总结/文摘

PROJECT SUMMARY/ABSTRACT In the proposed research, we address a problem that is common not just to melanoma, but also to other forms of cancer, such as prostate cancer, and that has been widely discussed recently. While we as dermatologists encourage patients to undergo skin cancer screening exams to detect melanoma early, it remains challenging to differentiate the truly aggressive from the indolent or nonclinical pigmented lesions. This is true even after a melanoma has been biopsied and examined under the microscope. As a result, there is massive over-diagnosis and overtreatment, specifically with respect to sentinel lymph node (SLN) biopsies, that is costly, has side effects, requires precious hospital infrastructure and induces substantial patient anxiety. Surprisingly, and despite decades of research on cancer, assessment of metastasis risk in primary cutaneous melanoma continues to be based primarily on tumor invasion depth (also referred to Breslow depth), a method that was introduced 45 years go. While Breslow depth tends to work well at the extreme ends of the spectrum, most melanomas fall into a grey zone where Breslow depth with or without additional tissue-derived and clinical variables (such as patient age) does not predict the true biology of melanoma well. Breslow depth continues to be popular because alternative methods, including molecular-based methods, are either ineffective, have not been appropriately validated or lack a strong biological rationale. This in turn inhibits the development of new and innovative therapies. Here we will study a method that quantifies changes in integrin-linked cell adhesion to better differentiate high-risk (defined as SLN positive melanoma) from biologically indolent melanoma. First, we will study consecutive cases of cutaneous melanoma from across the United States and Europe and correlate a molecular profile of cell adhesion with SLN status. Second, we will study how the inhibition of certain aspects of integrin adhesion affects melanoma growth and metastasis in vivo. We expect that our research will validate methods to identify high-risk melanoma that outperform the standard of care, reduce the rate of unnecessary SLN procedures and identify patients with high-risk melanoma overlooked by current procedures. Moreover, a better understanding of the molecular machinery that drives metastasis will create new therapeutic opportunities. The candidate’s long term goal is discover novel characteristics of malignant melanocytes that enable the development of new and innovative diagnostic methods and therapies. The mentored career development award will help the candidate acquire new methodological, professional and leadership skills to independently, successfully and meaningfully contribute to the fields of cell adhesion/cancer/melanoma research in the years to come. Specifically, the plan is to pursue the following training activities: 1.) Acquire expertise in studying melanoma using mouse models; use these models to test and optimize drugs and drugs combinations. 2.) Acquire experience in interpreting the histological features of melanoma; broaden my understanding of the biological concepts used by dermatopathologists to characterize melanoma. 3.) Acquire expertise in designing diagnostic biomarker studies; learn statistical methods, specifically methods that can be used to analyze complex datasets. 4.) Build the professional and leadership skills to bring together and lead an international consortium of melanoma investigators. The candidate will be mentored by a team of national experts in the field of cancer research. Mentoring and research will be carried out at the Mayo Clinic in Rochester, MN. Mayo Clinic offers core facility services for all mainstream standardized biomedical research methods. This includes tissue archives and bio-banking, animal housing and animal care, optical imaging, including high-end confocal microscopes, all methods related to histology, including RNA and DNA in-situ hybridization, targeted gene expression-based methods including microfluidic Fluidigm technology, and all mainstream ‘omics’ methods. All services are fully staffed with trained technicians. Moreover, there is scientific staff available to trouble-shoot experiments. These resources are all within walking distance from the candidate’s laboratory. Moreover, Mayo Clinic has a large staff of medical indexers, software programmers, application specialist and bio-information scientists. Because of the size of the clinic, there are medical specialists and subspecialists on hand for all areas of medicine.