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.

项目摘要/摘要在拟议的研究中，我们解决了一个不仅对黑色素瘤，而且对其他形式的癌症，例如前列腺癌，最近已广泛讨论。尽管作为皮肤科医生，我们鼓励患者参加皮肤癌筛查检查以检测早期黑色素瘤，将真正的侵略性与懒惰或非临床小猪病变。即使在黑色素瘤进行活检和检查之后，这也是如此在显微镜下。结果，有大量的过度诊断和过度治疗，特别是关于哨兵淋巴结（SLN）活检，这是昂贵的，具有副作用，需要珍贵医院基础设施并引起大量的患者动画。令人惊讶的是，对癌症的数十年研究，评估主要的转移风险皮肤黑色素瘤继续主要基于肿瘤侵袭深度（也称为 Breslow Depth），这是引入45年的一种方法。而布雷斯洛的深度往往可以很好地工作频谱的极端末端，大多数黑色素瘤落入了一个灰色区域，布雷斯洛深处有或没有其他组织衍生和临床变量（例如患者年龄）不会预测真实黑色素瘤生物学很好。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是无效的，尚未得到适当验证或缺乏强大的生物原理。这反过来抑制了新创新的发展疗法。在这里，我们将研究一种量化整联蛋白连接细胞粘合剂变化的方法将高风险（定义为SLN阳性黑色素瘤）与生物酸懒的黑色素瘤区分开。第一的，我们将研究来自美国和欧洲的连续皮肤黑色素瘤病例并将细胞粘附的分子谱与SLN状态相关联。第二，我们将研究整联蛋白粘附的某些方面的抑制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方法来确定高风险黑色素瘤护理标准，降低不必要的SLN程序的速度并确定具有高风险的患者黑色素瘤被当前程序忽略了。而且，更好地理解分子驱动转移的机械将创造新的治疗机会。候选人的长期目标是发现恶性黑色素细胞的新颖特征开发新的创新诊断方法和疗法。事业事业发展奖将帮助候选人获得新的方法论，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/黑色素瘤研究未来几年。具体而言，计划是追求在培训活动之后： 1.）获取使用小鼠模型研究黑色素瘤方面的专业知识；使用这些模型测试和优化药物和药物组合。 2.）获得解释黑色素瘤组织学特征的经验；拓宽我的对皮肤病理学家用来表征黑色素瘤的生物学概念的理解。 3.）获得设计诊断生物标志物研究的专业知识；学习统计方法，特别是可用于分析复杂数据集的方法。 4.）建立专业和领导能力，以团结并领导国际黑色素瘤研究者的财团。候选人将由癌症研究领域的国家专家团队考虑。指导和研究将在明尼苏达州罗切斯特的梅奥诊所进行。梅奥诊所优惠所有主流标准化生物医学研究方法的核心设施服务。这包括组织档案和生物银行，动物外壳和动物护理，光学成像，包括高端共聚焦显微镜，与组织学有关的所有方法，包括RNA和DNA杂交，靶向基因表达的方法，包括微流体流体技术，以及所有主流“幻象”方法。所有服务都配备了训练有素的技术人员。而且，有科学人员可用于故障射击实验。这些资源都在步行距离之内来自候选人的实验室。此外，梅奥诊所拥有大量的医疗指数，软件程序员，申请专家和生物信息科学家。由于诊所的大小，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

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

DOI：
10.1111/ijd.15125
发表时间：
2020-10
期刊：
International journal of dermatology
影响因子：
3.6
作者：
Quattrocchi E;Sominidi-Damodaran S;Murphree DH;Meves A
通讯作者：
Meves A

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