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

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

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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.

由于转移性进展的关键步骤之一需要肿瘤成功与其局部微环境相互作用，因此，靶向这种交叉对话可能是标准治疗方法的有吸引力的辅助药。目前，我们专注于开发针对相关肿瘤招募的宿主基质细胞的疗法。我们有一项IRB认可的生物存储库研究，以获取血液，骨髓和肿瘤以及邻近的正常组织，如果有恶性肿瘤和健康供体的患者。我们继续进行持续的研究，以测量和表征在癌症和其他慢性疾病中可能改变的循环骨髓衍生细胞。利用定量和功能测定，包括流式细胞仪和菌落形成单位测定法，我们正在评估儿科和成年恶性肿瘤患者中循环的骨髓衍生的祖细胞细胞群体。我们已经确定，在对原发性肿瘤进行手术切除时，循环骨髓衍生的细胞群有一系列可以增强转移性扩散的细胞群。我们继续在术后和术后一周内立即从患者那里收集血液样本，以更好地了解激增的性质以及如何最好地靶向。我们扩大了研究，以更好地了解造血干细胞生态位的变化，从而导致免疫环境改变，以应对生长的原发性肿瘤。现在，这些研究还包括监测造血和内皮祖细胞，还包括CD4和CD8 T细胞以及包括MDSC，M1和M2巨噬细胞（M1和M2巨噬细胞）。此外，我们测量肿瘤细胞释放的微囊泡和可能影响重要细胞行为的肿瘤基质细胞释放的微囊泡，并且已知对细胞 - 细胞通信至关重要。我们正在进行有关细胞在哪些细胞中进行哪些微泡及其特定含量的研究，并确定哪些是最有用的作为转移风险的生物标志物。我们继续与Sharon Savage博士的合作，检查Li Fraumeni综合征患者的循环骨髓衍生的细胞群，这是一种与肿瘤抑制p53丧失有关的高风险癌症易感综合征。我们正在招募患者，以确定这些骨髓衍生的细胞种群的变化是否预测了这些患者的肿瘤发展。我们正在监测年度癌症监测时骨髓衍生细胞的循环水平。我们还开发了测定方法来检查可以在存储的RNA样品中测量的生物学相关性，以便将结果数据与这些生物标志物相关联，以实现转移风险。我们已经建立了一个用于测试小儿肉瘤中微环境靶向疗法的临床前模型系统。利用EWINGS肉瘤异种移植肿瘤细胞系和同性横纹肌肉瘤细胞系，我们进行了流式细胞仪和免疫荧光，以证明髓样细胞流入肿瘤和过程前组织。我们还使用荧光素酶成像监测切除模型中的转移进程。以这种方式，可以在经过治疗和未经处理的组中遵循和比较，而无需多个终端终点，可以遵循和比较对可见转移的转移和进展。我们正在利用针对基质细胞的抑制剂进行专门评估对转移性进展的影响的临床前研究。现在，我们还具有肿瘤相关的成纤维细胞激活和基质细胞谱系追踪小鼠的标记，以便在此过程中监测这些细胞的激活。我们已经进行了地形小鼠实验，研究了髓样细胞和基质细胞的靶向，以确定它们对转移性进展的影响。这些临床前研究将回答这种治疗方法是否可能是靶向支持支持肿瘤进展的这些微环境肿瘤相关的细胞的好窗口。我们还建立了一个良好的体外模型，以了解肿瘤分泌因子对髓样细胞发育和功能的作用。这些研究允许研究髓样偏度和极化过程的潜在治疗抑制剂的功能。今年，与Brigitte Widemann合作，我们正在设计一项针对药物的肿瘤微环境的I期试验，尤其是针对复发固体瘤的小儿CFMS的新小分子抑制剂靶向CSF1R表达细胞。