Biomarkers and Therapeutic Targets in Angiogenesis and Metastasis

血管生成和转移中的生物标志物和治疗靶点

基本信息

批准号：
8938065
负责人：
Rosandra Kaplan
金额：
$ 51.36万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8938065
关键词：
Adjuvant Adult Aging-Related Process Area Biological Biological Assay Biological Markers Biological Models Blood Blood Vessels Blood specimen Bone Marrow Bone Marrow Neoplasms CD8B1 gene CSF1R gene Cell Communication Cell Line Cell Lineage Cells Childhood Chronic Disease Clinical Trials Collaborations Colony-Forming Units Assay Data Development Disease Disseminated Malignant Neoplasm Distant Drug Targeting Effectiveness Enrollment Epigenetic Process Evaluation Ewings sarcoma Excision Fibroblasts Flow Cytometry Growth and Development function Heart Diseases Hematopoietic Hematopoietic stem cells High-Risk Cancer Human Image Immune Immunofluorescence Immunologic Inflammatory Institutional Review Boards Investigation Li-Fraumeni Syndrome Longevity Longitudinal Studies Luciferases Malignant Neoplasms Measures Mediator of activation protein Mesenchymal Modeling Monitor Mus Mutation Myelogenous Myeloid Cells Nature Neoplasm Metastasis Normal tissue morphology Nutrient Operative Surgical Procedures Organ Transplantation Outcome Patients Phase I Clinical Trials Population Pre-Clinical Model Predisposition Primary Neoplasm Process Protein p53 RNA Recruitment Activity Recurrence Relapse Rhabdomyosarcoma Risk Role Sampling Site Solid Neoplasm Stem cells Stromal Cells Supporting Cell Syndrome T-Lymphocyte Testing Therapeutic Time Tissues Translational Research Tumor Cell Line Tumor Markers Vascular Diseases Wound Healing Xenograft procedure angiogenesis base bone circulation cell behavior design improved in vitro Model in vivo indexing inhibitor/antagonist macrophage monocyte neoplastic cell novel pre-clinical preclinical study progenitor prognostic repository research study response sarcoma small molecule standard care stem cell niche therapeutic target therapy design therapy development tissue regeneration tool tumor tumor microenvironment tumor progression tumorigenesis

项目摘要

As one of the crucial steps in metastatic progression requires tumor to successfully interact with its local microenvironment, it follows that targeting this cross-talk may be an attractive adjuvant to standard treatment approaches. We are currently focused on developing therapies that target the associated tumor recruited host stromal cells. We have an IRB approved biological repository study to obtain blood, bone marrow and tumor and adjacent normal tissue when available from patients with malignancy and healthy donors. We continue our on-going studies of measuring and characterizing the circulating bone marrow-derived cells that may be altered in the setting of cancer and other chronic diseases. Utilizing both quantification and functional assays, including flow cytometry and colony forming unit assays, we are assessing the circulating bone marrow-derived progenitor cell populations in pediatric and adult patients with malignancies. We have identified that at the time of surgical resection of the primary tumor there is a surge in circulating bone marrow-derived cell populations that can enhance metastatic spread. We continue to collect blood samples from patients immediately before and within the week post-operatively to better understand the nature of the surge and how best to target it. We have broadened our investigations to better understand the changes in the hematopoietic stem cell niche that results in alterations in immune milieu in response to a growing primary tumor. These studies now include in addition to monitoring hematopoietic and endothelial progenitor cells but also CD4 and CD8 T cells and myeloid cells including MDSCs and M1 and M2 macrophages. Furthermore, we measure circulating microvesicles released by tumor cells and associated tumor stromal cells that may impact important cell behavior and are known to be critical to cell-cell communication. We have on-going investigations as to which cells make which microvesicles and their particular content and determining which would be most useful as a biomarker for metastatic risk. We continue our collaboration with Dr. Sharon Savage to examine circulating bone marrow-derived cell populations in patients with Li Fraumeni syndrome, which is a high-risk cancer predisposition syndrome related to loss of tumor suppressor p53. We are enrolling patients in order to determine if changes in these bone marrow-derived cell populations predict tumor development in these patients. We are monitoring circulating levels of bone marrow-derived cells at the time of the yearly evaluation for cancer surveillance. We have also developed assays to examine biological correlates that can be measured in stored RNA samples in order to correlate outcome data with these biomarkers for metastatic risk. We have established a pre-clinical model system for testing microenvironment-targeting therapy in pediatric sarcomas. Utilizing a Ewings sarcoma xenograft tumor cell line and a syngeneic rhabdomyosarcoma cell line we have performed flow cytometry and immunofluorescence to demonstrate the influx of myeloid cells into the tumor and pre-metastatic tissues. We also monitor metastatic progression in a resection model using luciferase imaging. In this fashion, pre-metastatic, metastatic colonization and progression to visible metastasis can be followed and compared in treated and untreated groups without requiring multiple terminal end points. We are conducting pre-clinical investigations utilizing inhibitors targeting stromal cells specifically to assess impact on metastatic progression. We also now have a marker of tumor associated fibroblast activation and stromal cell lineage tracing mice in order to monitor activation of these cells in this process. We have performed seeral in vivo mouse experiments examining targeting of myeloid cells and stromal cells to determine their impact on metastatic progression. These pre-clinical studies will answer whether this approach to treatment maylikely be a good window for targeting the recruitment of these microenvironment tumor-associated cells that support tumor progression. We have also established a good in vitro model to understand the role of tumor-secreted factors on myeloid cell development and function. These studies allow for investigating function of potential therapeutic inhibitors of the myeloid skewing and polarization process. This year, in collaboration with Brigitte Widemann, we are designing a phase I trial of tumor microenvironment targeting drugs in particular targeting CSF1R expressing cells by a new small molecule inhibitor of cfms in pediatric patients with relapsed solid tumors.

由于转移进展的关键步骤之一需要肿瘤与其局部微环境成功相互作用，因此针对这种相互作用可能是标准治疗方法的有吸引力的辅助剂。我们目前专注于开发针对相关肿瘤招募的宿主基质细胞的疗法。我们进行了 IRB 批准的生物储存库研究，以获取来自恶性肿瘤患者和健康捐赠者的血液、骨髓、肿瘤和邻近正常组织。我们继续进行持续的研究，测量和表征循环骨髓衍生细胞，这些细胞可能在癌症和其他慢性疾病的情况下发生改变。利用定量和功能测定（包括流式细胞术和集落形成单位测定），我们正在评估患有恶性肿瘤的儿科和成人患者的循环骨髓来源的祖细胞群。我们发现，在手术切除原发肿瘤时，循环骨髓来源的细胞群会激增，从而增强转移扩散。我们继续在术前和术后一周内收集患者的血液样本，以更好地了解激增的性质以及如何最好地针对它。我们扩大了研究范围，以更好地了解造血干细胞生态位的变化，这些变化导致免疫环境发生变化，以应对不断生长的原发肿瘤。这些研究现在除了监测造血和内皮祖细胞外，还包括 CD4 和 CD8 T 细胞以及骨髓细胞，包括 MDSC 以及 M1 和 M2 巨噬细胞。此外，我们还测量了肿瘤细胞和相关肿瘤基质细胞释放的循环微泡，这些微泡可能影响重要的细胞行为，并且已知对细胞间通讯至关重要。我们正在持续研究哪些细胞产生哪些微泡及其特定内容，并确定哪些最适合作为转移风险的生物标志物。我们继续与 Sharon Savage 博士合作，检查 Li Fraumeni 综合征患者的循环骨髓来源细胞群，这是一种与肿瘤抑制因子 p53 缺失相关的高风险癌症易感综合征。我们正在招募患者，以确定这些骨髓来源细胞群的变化是否可以预测这些患者的肿瘤发展。我们在每年评估癌症监测时监测骨髓来源细胞的循环水平。我们还开发了检测生物相关性的方法，可以在储存的 RNA 样本中进行测量，以便将结果数据与这些转移风险的生物标志物相关联。我们建立了一个临床前模型系统，用于测试儿科肉瘤的微环境靶向治疗。利用尤文氏肉瘤异种移植肿瘤细胞系和同基因横纹肌肉瘤细胞系，我们进行了流式细胞术和免疫荧光分析，以证明骨髓细胞流入肿瘤和转移前组织。我们还使用荧光素酶成像监测切除模型中的转移进展。以这种方式，可以在治疗组和未治疗组中跟踪和比较转移前、转移性定植以及进展为可见转移，而不需要多个终点。我们正在利用针对基质细胞的抑制剂进行临床前研究，专门评估对转移进展的影响。我们现在还拥有肿瘤相关成纤维细胞激活和基质细胞谱系追踪小鼠的标记，以便监测这些细胞在此过程中的激活。我们进行了多次体内小鼠实验，检查骨髓细胞和基质细胞的靶向，以确定它们对转移进展的影响。这些临床前研究将回答这种治疗方法是否可能是针对招募这些支持肿瘤进展的微环境肿瘤相关细胞的良好窗口。我们还建立了良好的体外模型来了解肿瘤分泌因子对骨髓细胞发育和功能的作用。这些研究允许研究骨髓偏斜和极化过程的潜在治疗抑制剂的功能。今年，我们与 Brigitte Widemann 合作，设计了一项肿瘤微环境靶向药物的 I 期试验，特别是通过一种新的 cfms 小分子抑制剂在患有复发性实体瘤的儿科患者中靶向 CSF1R 表达细胞。