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.

项目概要/摘要在拟议的研究中，我们解决了一个不仅对于黑色素瘤而且对于黑色素瘤也很常见的问题。其他形式的癌症，例如前列腺癌，最近已得到广泛讨论。作为皮肤科医生，我们鼓励患者接受皮肤癌筛查检查以发现在早期黑色素瘤中，区分真正的侵袭性和惰性或惰性黑色素瘤仍然具有挑战性。即使在对黑色素瘤进行活检和检查后，非临床色素病变也是如此。结果，存在大量的过度诊断和过度治疗，特别是过度治疗。前哨淋巴结（SLN）活检费用昂贵，有副作用，需要珍贵的医院基础设施并引起患者极大的焦虑。令人惊讶的是，尽管对癌症进行了数十年的研究，但对原发性癌症转移风险的评估皮肤黑色素瘤仍然主要基于肿瘤浸润深度（也称为 Breslow 深度），这是 45 年前推出的方法，而 Breslow 深度往往在以下情况下效果很好。在光谱的最末端，大多数黑色素瘤落入灰色区域，其中布雷斯洛深度或没有额外的组织来源和临床变量（例如患者年龄）并不能预测真实的情况黑色素瘤的生物学深度仍然很受欢迎，因为替代方法，包括基于分子的方法，要么无效，要么未经适当验证，要么缺乏强有力的生物学原理，这反过来又抑制了新的和创新的发展。疗法。在这里，我们将研究一种量化整合素连接的细胞粘附变化的方法，以更好地区分高风险（定义为 SLN 阳性黑色素瘤）和生物学惰性黑色素瘤。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特征与 SLN 状态相关联其次，我们将研究如何将细胞粘附的分子特征与 SLN 状态相关联。整合素粘附某些方面的抑制会影响体内黑色素瘤的生长和转移。期望我们的研究将验证识别高风险黑色素瘤的方法，其效果优于现有方法护理标准，减少不必要的前哨淋巴结手术率并识别高危患者此外，对分子的更好理解也被当前的手术所忽视。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，使开发新的和创新的诊断方法和疗法。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具体来说，该计划是在未来几年进行粘连/癌症/黑色素瘤研究。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；使用这些模型进行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；了解皮肤病理学家用来表征黑色素瘤的生物学概念。 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.) 培养专业和领导技能，以聚集并领导国际化的组织黑色素瘤研究人员联盟。候选人将接受癌症研究领域国家专家团队的指导。指导和研究将在明尼苏达州罗彻斯特的梅奥诊所进行。所有主流标准化生物医学研究方法的核心设施服务。组织档案和生物库、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，包括微流控 Fluidigm 技术，以及所有主流的“组学”方法均配备了训练有素的技术人员。可以对实验进行故障排除的科学人员这些资源都在步行距离之内。此外，梅奥诊所拥有大量的医疗索引器、软件。由于诊所的规模，程序员、应用专家和生物信息科学家。所有医学领域都有医学专家和亚专科医生在场。

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）

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：
发表时间：
2024-04
期刊：
影响因子：
3.6
作者：
Meves, Elena S;Meves, Alexander
通讯作者：
Meves, Alexander

FAK auto-phosphorylation site tyrosine 397 is required for development but dispensable for normal skin homeostasis.

FAK 自磷酸化位点酪氨酸 397 是发育所必需的，但对于正常皮肤稳态来说是可有可无的。

DOI：
发表时间：
2018
期刊：
影响因子：
3.7
作者：
Heim, Joel B;McDonald, Cera A;Wyles, Saranya P;Sominidi;Squirewell, Edwin J;Li, Ming;Motsonelidze, Catherine;Böttcher, Ralph T;van Deursen, Jan;Meves, Alexander
通讯作者：
Meves, Alexander

Clinical and histopathologic manifestations of solid organ transplantation-associated graft-versus-host disease involving the skin: A single-center retrospective study.

涉及皮肤的实体器官移植相关移植物抗宿主病的临床和组织病理学表现：单中心回顾性研究。

DOI：
发表时间：
2018-11
期刊：
影响因子：
1.7
作者：
Kim, Grace Y;Schmelkin, Leah A;Davis, Mark D;El;Wieland, Carilyn N;Leise, Michael D;Meves, Alexander;Lehman, Julia S
通讯作者：
Lehman, Julia S

Keloids: a review of therapeutic management.

瘢痕疙瘩：治疗管理综述。