Characterizing lymphatic micrometastases: prognostic and therapeutic implications

淋巴微转移的特征：预后和治疗意义

• 批准号: 8146385
• 负责人: TIMOTHY P PADERA
• 金额: $ 261.33万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8146385
• 关键词: Address; Affect; Animal Model; Area; Award; Biological; Biology; Cancer Etiology; Chronic; Data; Disease; Distant; Engineering; Excision; Growth; Individual; Lead; Lymphatic; Lymphatic Metastasis; Metabolism; Micrometastasis; Modeling; Molecular; Monitor; Neoplasm Metastasis; Organ; Outcome; Patient Care; Patients; Primary Neoplasm; Problem Solving; Qualifying; Research; Seeds; Site; Staging; Survival Rate; Techniques; Therapeutic; Therapeutic Intervention; Translating; United States National Institutes of Health; Vascularization; Work; abstracting; base; cancer cell; cancer therapy; clinically relevant; design; experience; improved; innovation; intravital microscopy; lymph nodes; mortality; neoplastic cell; novel; prevent; prognostic; public health relevance; response; skills; success; tumor; tumor growth

DESCRIPTION (Provided by the applicant) Abstract: Metastasis remains the major cause of cancer mortality, but breakthroughs in our understanding of the molecular and cellular mechanisms regulating metastasis have yet to be broadly translated into improved survival rates in patients with metastatic disease. The challenge is how to treat cancer cells that have spread to lymph nodes or distant organs in order to prevent their growth and ideally eradicate them from the body. Most cancer therapies are developed against the primary tumor growing in its native microenvironment. However, it is clear that the local microenvironment in which tumor cells grow greatly affects the growth rate, metabolism, vascularization and ultimately response to therapeutic intervention. In this NIH Director's New Innovator Award, I propose to biologically characterize the growth of metastatic tumor cells in lymph nodes starting from individual seeded cancer cells. This research is motivated by basic, critically important questions that will ultimately help clinicians better manage metastatic disease: i) What are the biological triggers for metastatic growth in lymph nodes? ii) Are lymph node metastases clonal or are multiple cancer cells needed to initiate growth in the node? iii) Is there a therapeutic benefit to the removal lymph nodes with only a few cancer cells? iv) Do lymph node metastases seed distant sites leading to further dissemination? To address these questions, I will utilize our newly developed chronic lymph node window in order to study spontaneously disseminated cancer cells in the lymph node. This innovative window model overcomes a major barrier to research and allows us to monitor the earliest stages of metastatic growth in lymph nodes, characterize the biological triggers for growth from individually seeded cancer cells, determine whether lymphatic metastasis are clonal and investigate whether lymph node metastases can further disseminate. In this way, we will use novel techniques to address the problem of lymphatic metastasis in a new way-characterizing a growing metastasis in its new microenvironment. These clinically driven projects will yield data to help i) better predict outcome and design therapeutic courses for patients with micrometastatic disease in their lymph nodes, as well as ii) uncover the underlying biology of metastatic tumor growth in the lymph nodes, potentially leading to novel targets for the treatment of lymphatic metastasis. Based on my foundational background in engineering, along with over 12 years experience innovating intravital microscopy techniques and animal models to study critical problems in tumor metastasis, I am uniquely qualified to lead this effort. I have used these skills to creatively solve problems that have hindered research in critical areas of lymphatic biology and lymphatic metastasis. I have shown that I am willing to challenge conventional paradigms and keep my work focused on clinically relevant problems that need basic biological discoveries to drive new therapies. I have also shown I can work with clinicians to impact patient care. I will continue to build on my past successes with this proposed NIH Director's New Innovator Award and hopefully have a positive impact on the treatment of patients with lymphatic metastases. Public Health Relevance: Metastasis remains the major cause of cancer mortality posing the challenge of how to treat cancer cells that have spread to lymph nodes or distant organs in order to prevent their growth and ideally eradicate them from the body. To answer this challenge, I will utilize our newly developed chronic lymph node window to characterize the triggers for the growth of seeded cancer cells and investigate whether lymph node metastasis can further disseminate. These clinically driven projects will yield data to i) better predict outcome and design therapeutic courses for patients with lymphatic metastases, as well as ii) uncover the underlying biology of metastatic tumor growth in the lymph nodes, leading to novel targets for the treatment of lymphatic metastasis.

描述（申请人提供） 摘要：转移仍然是癌症死亡率的主要原因，但是在我们对调节转移的分子和细胞机制的理解中的突破尚未广泛转化为转移性疾病患者的生存率的提高。挑战是如何处理扩散到淋巴结或远处器官的癌细胞，以防止其生长并理想地从体内消除它们。大多数癌症疗法是针对其本地微环境中原发性肿瘤发展的。但是，很明显，肿瘤细胞生长的局部微环境会极大地影响生长速率，代谢，血管形成以及最终对治疗干预的反应。在NIH总监的新创新奖中，我建议从生物学上表征从单个种子癌细胞开始的淋巴结中转移性肿瘤细胞的生长。这项研究是出于基本，至关重要的问题的动机，这些问题最终将帮助临床医生更好地管理转移性疾病：i）淋巴结转移性增长的生物学触发因素是什么？ ii）淋巴结转移是克隆的，还是需要多个癌细胞来启动该节点的生长？ iii）仅几个癌细胞的去除淋巴结有治疗益处吗？ iv）淋巴结转移是否导致进一步传播的种子远处位点？为了解决这些问题，我将利用我们新开发的慢性淋巴结窗口，以研究淋巴结中自发传播的癌细胞。这种创新的窗口模型克服了研究的主要障碍，并使我们能够监测淋巴结转移性生长的最早阶段，表征了来自单独种子癌细胞生长的生物触发器，确定淋巴转移是克隆的，并研究淋巴结转移酶是否可以进一步散射。通过这种方式，我们将使用新颖的技术来解决淋巴转移的问题，以新的方式表征其新的微环境中不断增长的转移。这些临床驱动的项目将产生数据以帮助i）更好地预测其淋巴结中微转移性疾病患者的预后和设计治疗课程，以及II）识别淋巴结中转移性肿瘤生长的基本生物学，有可能导致淋巴转移的新靶标。根据我的工程基础背景，以及12年以上的经验，经验创新的插入式显微镜技术和动物模型来研究肿瘤转移的关键问题，我具有独特的资格来领导这项工作。我使用这些技能来创造性地解决了阻碍淋巴生物学和淋巴转移的关键领域研究的问题。我已经表明，我愿意挑战常规范式，并将工作集中在需要基本生物学发现以推动新疗法的临床相关问题上。我还表明，我可以与临床医生一起影响患者护理。我将通过这项拟议的NIH董事的新创新者奖，继续以自己的过去成功为基础，并希望对淋巴转移患者的治疗产生积极影响。 公共卫生相关性：转移仍然是癌症死亡率的主要原因，构成了如何治疗已经扩散到淋巴结或远处器官的癌细胞的挑战，以防止其生长并理想地从体内消除它们。为了应对这一挑战，我将利用我们新开发的慢性淋巴结窗口来表征种子癌细胞生长的触发因素，并研究淋巴结转移是否可以进一步传播。这些临床驱动的项目将为i）提供数据）更好地预测淋巴转移患者的预后和设计治疗课程，以及ii）识别淋巴结转移性肿瘤生长的潜在生物学，从而导致了治疗淋巴转移的新靶标。