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Precision Medicine by Targeting Cell Adhesion in Melanoma

通过靶向黑色素瘤细胞粘附的精准医学

基本信息

批准号：
10179329
负责人：
Alexander Meves
金额：
$ 17.09万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10179329
关键词：
Address Adhesions Adjuvant Therapy Affect Age Animal Housing Anxiety Area Biological Biology Biomedical Research Biopsy Biopsy Specimen Breslow Thickness Cell Adhesion Cell Communication Characteristics Clinic Clinical Clinical Data Complex Computer software Core Facility Cutaneous Melanoma Cytotoxic T-Lymphocytes DNA Data Set Decision Making Dermatologist Development Diagnosis Diagnostic Diagnostic Procedure Drug Combinations Europe Extracellular Matrix Fibronectin Receptors Fibronectins Gene Expression Goals Growth Hand Healthcare Histologic Histology Hospitals Immune checkpoint inhibitor Immunotherapy In Situ Hybridization Indolent Infiltration Infrastructure Innovative Therapy Integrins International K-Series Research Career Programs Knowledge Laboratories Lead Leadership Lesion Life Link Mainstreaming Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Medical Staff Medicine Melanoma Cell Mentors Methodology Methods Microfluidics Microscope Mitotic Modeling Molecular Molecular Profiling Myofibroblast Names Neoplasm Metastasis Oncogenes Organ Patients Physicians Pigments Positive Lymph Node Procedures Publishing RNA Relapse Research Research Methodology Research Personnel Resistance Resources Risk Scientist Screening for Skin Cancer Sentinel Lymph Node Sentinel Lymph Node Biopsy Services Side Skin Cancer Specialist Standardization Statistical Methods Statistical Models Structure T-Lymphocyte Techniques Technology Testing Therapeutic Thick Thinness Tissues Training Training Activity Translating Tumor Cell Invasion United States Up-Regulation Walking Work animal care anti-PD1 therapy anticancer research base biological systems cancer cell cost design diagnostic biomarker draining lymph node experience experimental study falls high risk in vivo in vivo Model indexing innovation insight lymph nodes medical specialist melanocyte melanoma mouse model novel novel therapeutic intervention novel therapeutics optical imaging overtreatment precision medicine prevent response risk stratification side effect skills standard of care statistical learning tissue archive

项目摘要

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.

项目总结/摘要在拟议的研究中，我们解决了一个问题，这不仅是常见的黑色素瘤，但也其他形式的癌症，如前列腺癌，最近已被广泛讨论。而作为皮肤科医生，我们鼓励患者接受皮肤癌筛查检查，早期黑色素瘤，它仍然具有挑战性，以区分真正的侵略性从惰性或非临床色素性病变。这是真实的，即使在黑色素瘤已经活检和检查在显微镜下。因此，有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，其昂贵，具有副作用，需要宝贵的医院基础设施，并引起大量的病人焦虑。令人惊讶的是，尽管对癌症进行了数十年的研究，但对原发性肝癌转移风险的评估仍然存在不足。皮肤黑色素瘤仍然主要基于肿瘤侵袭深度（也称为布雷斯洛深度），一种方法，介绍了45年去.虽然Breslow深度往往工作良好，在光谱的极端，大多数黑色素瘤落入灰色区域，其中Breslow深度与或如果没有额外的组织来源和临床变量（如患者年龄），黑色素瘤的生物学Breslow深度仍然很受欢迎，因为替代方法，包括基于分子的方法，要么是无效的，没有得到适当的验证，缺乏强有力的生物学依据。这反过来又抑制了新的和创新的发展。治疗在这里，我们将研究一种方法，量化的变化，整合素连接的细胞粘附，以更好地区分高风险（定义为SLN阳性黑色素瘤）与生物学惰性黑色素瘤。第一、我们将研究来自美国和欧洲的皮肤黑色素瘤的连续病例并将细胞粘附的分子谱与SLN状态相关联。第二，我们将研究如何抑制整联蛋白粘附的某些方面影响体内黑素瘤生长和转移。我们我希望我们的研究能够验证识别高风险黑色素瘤的方法，护理标准，降低不必要的SLN手术率，并识别高风险患者黑色素瘤被目前的治疗方法所忽视。此外，更好地了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，开发新的和创新的诊断方法和疗法。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粘附/癌症/黑色素瘤研究在未来几年。具体来说，该计划是追求以下培训活动： 1.）的人。获得使用小鼠模型研究黑色素瘤的专业知识;使用这些模型来测试和优化药物和药物组合。 2.）的情况。获得解释黑色素瘤组织学特征的经验;拓宽我的视野了解皮肤病理学家用来描述黑色素瘤的生物学概念。 3.）第三章获得设计诊断生物标志物研究的专业知识;学习统计方法，特别是可以用来分析复杂数据集的方法。 4.）建立专业和领导技能，汇集和领导一个国际黑色素瘤研究者联盟。候选人将由癌症研究领域的国家专家小组指导。指导和研究将在明尼苏达州罗切斯特的马约诊所进行。马约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，动物饲养和动物护理，光学成像，包括高端共聚焦显微镜，所有与组织学相关的方法，包括RNA和DNA原位杂交，基于靶向基因表达的方法，包括微流体Fluidigm技术，以及所有主流的“组学”方法。所有服务都配备了训练有素的技术人员。此外，科学工作人员可用于故障排除实验。这些资源都在步行距离内从候选人的实验室。此外，马约诊所拥有大量的医疗索引人员、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医生。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Deep learning for dermatologists: Part II. Current applications.

DOI：
10.1016/j.jaad.2020.05.053
发表时间：
2022-12
期刊：
Journal of the American Academy of Dermatology
影响因子：
13.8
作者：
Puri P;Comfere N;Drage LA;Shamim H;Bezalel SA;Pittelkow MR;Davis MDP;Wang M;Mangold AR;Tollefson MM;Lehman JS;Meves A;Yiannias JA;Otley CC;Carter RE;Sokumbi O;Hall MR;Bridges AG;Murphree DH
通讯作者：
Murphree DH

Prognostic significance of sentinel lymph node status in thin melanoma: a retrospective analysis.

薄黑色素瘤前哨淋巴结状态的预后意义：回顾性分析。

DOI：
10.1111/ijd.17000
发表时间：
2024
期刊：
International journal of dermatology
影响因子：
3.6
作者：
Meves,ElenaS;Meves,Alexander
通讯作者：
Meves,Alexander

Deep learning for dermatologists: Part I. Fundamental concepts.

DOI：
10.1016/j.jaad.2020.05.056
发表时间：
2022-12
期刊：
Journal of the American Academy of Dermatology
影响因子：
13.8
作者：
Murphree DH;Puri P;Shamim H;Bezalel SA;Drage LA;Wang M;Pittelkow MR;Carter RE;Davis MDP;Bridges AG;Mangold AR;Yiannias JA;Tollefson MM;Lehman JS;Meves A;Otley CC;Sokumbi O;Hall MR;Comfere N
通讯作者：
Comfere N

Validation of CP-GEP (Merlin Assay) for predicting sentinel lymph node metastasis in primary cutaneous melanoma patients: A U.S. cohort study.

DOI：
10.1111/ijd.15594
发表时间：
2021-07
期刊：
International journal of dermatology
影响因子：
3.6
作者：
Yousaf A;Tjien-Fooh FJ;Rentroia-Pacheco B;Quattrocchi E;Kobic A;Tempel D;Kolodney M;Meves A
通讯作者：
Meves A

β3 integrin immunohistochemistry as a method to predict sentinel lymph node status in patients with primary cutaneous melanoma.