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

• 批准号: 8763462
• 负责人: Rosandra Kaplan
• 金额: $ 46.96万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 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/8763462
• 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; Breast Carcinoma; CD34 gene; Cell Lineage; Cells; Childhood; Chronic Disease; Clinical Trials; Collaborations; Colony-Forming Units Assay; Data; Development; Disease; Disease Progression; Disseminated Malignant Neoplasm; Distant; Drug Targeting; Effectiveness; Enrollment; Epigenetic Process; Evaluation; Ewings sarcoma; Excision; Fibroblasts; Flow Cytometry; Genes; Growth and Development function; Heart Diseases; Hematopoietic; Hematopoietic stem cells; High-Risk Cancer; Human; Image; Immunofluorescence Immunologic; Inflammatory; Institutional Review Boards; Investigation; Large Intestine Carcinoma; Li-Fraumeni Syndrome; Longevity; Longitudinal Studies; Luciferases; Malignant Neoplasms; Measures; Mediator of activation protein; Mesenchymal; Modeling; Monitor; Mus; Mutation; 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; Prognostic Marker; Protein p53; RNA; Recruitment Activity; Recurrence; Relapse; Risk; Role; Sampling; Site; Solid Neoplasm; Stem cells; Stromal Cells; Supporting Cell; Syndrome; Testing; Time; Tissues; Translational Research; Tumor Burden; Tumor Cell Line; Tumor Markers; Tumor-Derived; Vascular Diseases; Wound Healing; Xenograft procedure; angiogenesis; base; bone circulation; improved; indexing; inhibitor/antagonist; monocyte; novel; pre-clinical; preclinical study; progenitor; prognostic; repository; response; sarcoma; standard care; therapeutic target; therapy design; therapy development; tissue regeneration; tool; tumor; tumor microenvironment; tumor progression; tumorigenesis

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 now 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 an established 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 found a validated gene set in hematopoietic progenitor cells from patients with cancer from our microarray data from isolated CD34 cells from breast and colorectal carcinoma patients compared to healthy controls. The specific changes in these cells may help to serve as prognostic markers of disease progression as well as response to therapies. We have established a pre-clinical model system for testing microenvironment-targeting therapy in pediatric sarcomas. Utilizing a Ewings sarcoma xenograft tumor 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 established this year monitoring metastatic progression in a syngeneic 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 will perform these studies at the time of surgical resection of the primary tumor when overall tumor burden is low but metastatic risk is high. These pre-clinical studies will answer whether this approach to treatment may likely be a good window for targeting the recruitment of these bone marrow-derived tumor-associated cells that support tumor progression. Ultimately, I plan, in collaboration with Brigitte Widemann, to establish a phase I trial of tumor microenvironment targeting drugs 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。现在，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。我们与Sharon Savage博士建立了合作，以检查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倾向综合征。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。我们发现，与健康对照组相比，我们发现了来自乳腺癌和结直肠癌患者的分离的CD34细胞的癌症患者的造血祖细胞中的经过验证的基因。这些细胞中的特定变化可能有助于作为疾病进展的预后标记以及对疗法的反应。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，我们进行了流式细胞术和免疫荧光，以证明髓样细胞流入肿瘤和静脉前组织。我们还建立了今年使用荧光素酶成像在同步模型中监测转移进程的。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。当总体肿瘤负担低，但转移风险很高时，我们将在对原发性肿瘤进行手术切除时进行这些研究。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骨髓衍生的肿瘤相关细胞的良好窗口。最终，我计划与Brigitte Widemann合作，建立I期针对肿瘤微环境靶向药物的小儿固体肿瘤患者的试验。