Precision Medicine by Targeting Cell Adhesion in Melanoma

项目摘要/摘要 在这项拟议的研究中，我们解决了一个不仅对黑色素瘤很常见，而且对 其他形式的癌症，如前列腺癌，最近得到了广泛的讨论。而当 作为皮肤科医生，我们鼓励患者接受皮肤癌筛查，以发现 早期黑色素瘤，区分真正的侵袭者和懒惰的或 非临床色素性皮损。即使在对黑色素瘤进行活组织检查后也是如此。 在显微镜下。结果，出现了大量的过度诊断和过度治疗，特别是 关于前哨淋巴结(SLN)活检，这是昂贵的，有副作用的，需要宝贵的 医院的基础设施，并引发大量的患者焦虑。 令人惊讶的是，尽管对癌症进行了数十年的研究，但对原发肿瘤转移风险的评估 皮肤黑色素瘤仍然主要基于肿瘤的侵袭深度(也称为 Breslow Depth)，这是一种引入了45年的方法。而Breslow Depth往往在以下方面工作良好 在光谱的两端，大多数黑色素瘤都属于灰色区域，在那里Breslow深度或 没有额外的组织衍生和临床变量(如患者年龄)并不能预测真实的 黑色素瘤的生物学很好。布雷斯洛深度继续流行，因为替代方法， 包括基于分子的方法，要么无效，要么没有得到适当的验证，要么 缺乏强有力的生物学基础。这反过来又抑制了新的和创新的发展 治疗。 在这里，我们将研究一种量化整合素连接的细胞黏附变化的方法，以更好地 区分高危黑色素瘤(定义为SLN阳性黑色素瘤)和生物学惰性黑色素瘤。第一, 我们将研究美国和欧洲各地皮肤黑色素瘤的连续病例 并将细胞黏附的分子图谱与SLN状态相关联。第二，我们将研究如何 抑制整合素黏附的某些方面会影响黑色素瘤的生长和体内转移。我们 预计我们的研究将验证识别高危黑色素瘤的方法，这些方法的表现优于 护理标准，降低不必要的SLN手术比率，并识别高危患者 黑色素瘤被目前的程序忽视了。此外，更好地理解分子 驱动转移的机制将创造新的治疗机会。 候选人的长期目标是发现恶性黑素细胞的新特征，使其能够 开发新的和创新的诊断方法和治疗方法。被指导的职业生涯 发展奖将帮助候选人获得新的方法、专业和领导力 独立、成功和有意义地为细胞领域做出贡献的技能 未来几年的粘连/癌症/黑色素瘤研究。具体地说，该计划是追求 以下培训活动： 1)获得使用小鼠模型研究黑色素瘤的专业知识；使用这些模型测试和 优化药品和用药组合。 2.)获得解释黑色素瘤组织学特征的经验；拓宽我的 理解皮肤科医生用来描述黑色素瘤特征的生物学概念。 3.)获得设计诊断生物标记物研究的专业知识；学习统计方法， 特别是可用于分析复杂数据集的方法。 4.)培养专业和领导技能，以汇聚和领导国际 黑色素瘤调查员联盟。 候选人将接受癌症研究领域的国家专家团队的指导。 指导和研究将在明尼苏达州罗切斯特市的梅奥诊所进行。梅奥诊所提供 为所有主流标准化生物医学研究方法提供核心设施服务。这包括 组织档案和生物银行、动物住所和动物护理、光学成像，包括高端 共聚焦显微镜，所有与组织学有关的方法，包括RNA和DNA原位杂交， 基于靶向基因表达的方法，包括微流控技术和ALL 主流的“组学”方法。所有服务都配备了训练有素的技术人员。此外，还有 科学人员可以为实验排忧解难。这些资源都在步行的距离内。 从候选人的实验室。此外，梅奥诊所拥有一大批医疗索引器、软件 程序员、应用专家和生物信息科学家。因为诊所的规模， 所有医学领域都有医学专家和专科专家。

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.