Targeting lymph node metastases to prevent cancer progression

本行政补充将支持完成R 01 CA 214913的当前目标。完成 当前的《目标》还将提供初步数据，以响应《A0更新概要声明》 应用程序.这些初步数据将加强续签申请的A1提交。突破 在我们对调节转移的分子和细胞机制的认识中， 转化为提高转移性疾病患者的生存率。癌症的淋巴结转移 患者预后较差，建议进行全身治疗。但目前尚不清楚 淋巴转移是否只是预测性的，或者它们是否在癌症进展中起作用， 出现远处转移。有证据表明，治疗淋巴结转移可提高 一些病人。本文提出的工作旨在建立对淋巴结转移的生物学理解， 为了确定它们在疾病进展中的作用，并确定新的治疗干预措施，以改善患者的 生存最近，我们发现淋巴结转移不需要血管生成生长， 对抗血管生成治疗有反应。我们将建立在我们独特的专业知识，解决为什么淋巴结 转移是如此强的预后指标，并探讨淋巴结转移如何驱动癌症 进展具体来说，我们将检验淋巴结转移扩散到远处的假设 (Aim 1）并抑制免疫系统发展和维持抗肿瘤免疫的能力（目的2）。我们 我们将使用创新的动物模型来实现我们的目标，这些动物模型允许最先进的活体显微镜检查， 自发性淋巴结转移在目标1中，我们将确定癌细胞是否利用成纤维细胞 淋巴结中的网状细胞内衬管道系统，以血管为家并扩散到远处。我们将 试图阻止这一进程。在目标2中，我们将确定转移性淋巴结是否保留了 启动对新抗原的免疫反应。进一步，我们将确定免疫抑制的机制 转移性淋巴结我们将尝试增加淋巴结转移的免疫效应功能， 根除淋巴结疾病和刺激全身抗肿瘤免疫。为达致这些目标，我们会 有更好的淋巴结集中的治疗选择，以限制癌症从淋巴结的生长和扩散 从而为患者提供更好的结果。Padera博士是淋巴管活体显微镜的专家 淋巴结转移系统和机制。实现这些目标的关键因素至关重要 成像设备、复杂的动物模型和功能性免疫测定，所有这些都可在PI中获得 实验室此外，组建的团队拥有互补的专业知识，使他们能够克服任何 在项目过程中出现的问题，使我们能够独特地解决这些临床驱动的问题。与 我们的研究完成后，我们将能够更好地遏制和根除淋巴结转移， 转移性癌症患者的生存率。

This administrative supplement will support the completion of the current Aims of R01CA214913. Completing the current Aims will also provide preliminary data to respond to the Summary Statement of the A0 renewal application. These preliminary data will strengthen the A1 submission of the renewal application. Breakthroughs in our knowledge of the molecular and cellular mechanisms regulating metastasis have yet to be broadly translated into improved survival rates for patients with metastatic disease. Lymph node metastasis in a cancer patient brings with it a poorer prognosis and the recommendation for systemic therapy. However, it is unclear whether lymphatic metastases are only predictive or whether they play a role in cancer progression and the emergence of distant metastases. Evidence shows that treating lymph node metastases improves survival in some patients. The work proposed here aims to build a biological understanding of lymph node metastases in order to define their role in disease progression and identify new therapeutic interventions to improve patient survival. Recently, we have shown that lymph node metastases do not require angiogenesis to grow and do not respond to anti-angiogenic therapy. We will build upon our unique expertise by addressing why lymph node metastasis are such strong prognostic indicators and explore how lymph node metastasis drive cancer progression. Specifically, we will test the hypotheses that lymph node metastases disseminate to distant sites (Aim 1) and inhibit the ability of the immune system to develop and maintain anti-tumor immunity (Aim 2). We will accomplish our goals using innovative animal models that allow state-of-the-art intravital microscopy of spontaneous lymph node metastasis. In Aim 1, we will determine whether cancer cells utilize the fibroblastic reticular cell-lined conduit system in lymph nodes to home to blood vessels and spread to distant sites. We will attempt to block this process. In Aim 2, we will determine whether metastatic lymph nodes retain the ability to initiate immune responses to new antigens. Further, we will determine the mechanism of immune suppression in metastatic lymph nodes. We will attempt to increase immune effector function in lymph node metastases to eradicate lymph node disease and stimulate systemic anti-tumor immunity. In completing these aims, we will have better lymph node focused therapeutic options to limit the growth and spread of cancer from lymph nodes and thus provide better outcomes for patients. Dr. Padera is an expert in intravital microscopy of the lymphatic system and mechanisms of lymph node metastasis. Critical elements to achieving these goals are intravital imaging equipment, complex animal models and functional immunological assays, all available in the PI’s laboratory. In addition, the assembled team has complementary expertise that will enable them to overcome any problems that occur during the project, uniquely positioning us to address these clinically driven questions. With the completion of our studies, we will be able to better contain and eradicate lymph node metastasis to extend survival for patients with metastatic cancer.