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: 10014620
• 负责人: Rosandra Kaplan
• 金额: $ 53.7万
• 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/10014620
• 关键词: Adjuvant; Adjuvant Therapy; Adult; Aging; Area; Biological; Biological Assay; Biological Markers; Biological Models; Blood; Blood Vessels; Bone Marrow; Bone Marrow Neoplasms; CD8-Positive T-Lymphocytes; CSF1R gene; Cell Communication; Cell Line; Cell Lineage; Cells; Childhood; Chronic Disease; Collaborations; Colony-Forming Units Assay; Colony-Stimulating Factors; Cytotoxic T-Lymphocytes; Data; Development; Disease; Disseminated Malignant Neoplasm; Distant; Effectiveness; Endothelial Cells; Endothelium; Enrollment; Epigenetic Process; Evaluation; Ewings sarcoma; Excision; Extracellular Matrix; FLT3 gene; Fibrinogen; Fibroblasts; Flow Cytometry; Giant Cell Tumors; Growth; Growth and Development function; Heart Diseases; Hematopoietic; Hematopoietic stem cells; High-Risk Cancer; Human; Image; Immune; Immune Targeting; Immune response; Immune system; Immunofluorescence Immunologic; Immunotherapy; Inflammatory; Institutional Review Boards; Investigation; Lead; Li-Fraumeni Syndrome; Longevity; Longitudinal Studies; Luciferases; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Mesenchymal; Modeling; Molecular; Monitor; Mus; Mutation; Myelogenous; Myeloid Cells; NF1 gene; Neoplasm Metastasis; Neurofibrosarcoma; Normal tissue morphology; Organ Transplantation; Outcome; Patients; Pericytes; Phase; Play; Plexiform Neurofibroma; Population; Pre-Clinical Model; Predisposition; Primary Neoplasm; Process; Protein p53; RNA; Radiation; Recurrence; Relapse; Rhabdomyosarcoma; Risk; Role; Sampling; Site; Stem cells; Stromal Cells; Supporting Cell; Syndrome; Testing; Therapeutic; Time; Tissues; Translational Research; Transplant-Related Disorder; Treatment Efficacy; Tumor Cell Line; Tumor Immunity; Tumor Markers; Vascular Diseases; Wound Healing; angiogenesis; base; bone circulation; cell behavior; chemotherapy; childhood sarcoma; clinical investigation; conventional therapy; cytotoxicity; experimental study; fighting; hematopoietic stem cell niche; high risk; improved; in vitro Model; in vivo; individualized medicine; inhibitor/antagonist; macrophage; mast cell; microvesicles; monocyte; myeloid cell development; neoplastic cell; osteosarcoma; pediatric patients; pre-clinical; preclinical study; predictive tools; progenitor; prognostic tool; receptor; recruit; repository; response; specific biomarkers; standard care; targeted treatment; therapeutic target; therapy design; therapy development; tissue regeneration; tumor; tumor microenvironment; tumor progression; tumor xenograft; 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 have an IRB approved biological repository study to obtain blood, bone marrow, 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 progenitor, immune, endothelial and mesenchymal 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 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 and stromal cell populations. Furthermore, we measure circulating microvesicles released by tumor cells and associated tumor hematopoeitic and 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. Our recent studies have determined host cell plasticity and cell state determine the microvesicles released from these cells and this plasticity in perivascular cells play key roles in regulating metastasis. We are currently investigating markers of this perivascular cell plasticity as a predictor of metastasis and response to conventional therapies and immune based therapies. 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 (EWS) xenograft tumor cell line and two syngeneic models- rhabdomyosarcoma (RMS) cell line and an osteosarcoma (OS) cell line we have performed flow cytometry and immunofluorescence to demonstrate the influx of myeloid cells and alterations in stromal cell populations in 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 cell plasticity 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 serial in vivo mouse experiments examining targeting of myeloid cells and stromal cells to determine their impact on metastatic progression. We are using different investigational agents to determine their specific impact on each microenvironmental cell. These pre-clinical studies will answer whether this approach to treatment may likely be a good window for targeting the recruitment of these microenvironment tumor-associated cells that support tumor progression. Our studies using a colony stimulating factor -one receptor (csf1-R) inhibitor revealed that these models of RMS and Ewings sarcoma secrete a good deal of CSF-1 and lead to the recruitment of CSF-1R expressing cells. These cells are found in early metastatic sites and are immune suppressive and can protect disseminated tumor cells from cytotoxic T cell activity. We are working on developing approaches to promoting myeloid based anti-tumor immunity and performing studies to determine the critical effectors of this cytotoxicity. We have also established a good in vitro model to understand the role of tumor-secreted factors on myeloid cell development and stromal cell plasticity and function and investigating different approaches to targeting this process. These studies allow for investigating function of potential therapeutic inhibitors of the myeloid skewing and polarization process and the activation and expansion of specific perivascular cell populations that promote metastasis. This year we have completed the Phase I portion of Pexidartinib which inihibits FLT3, Kit and CSF1R. We are now planning enrollment on the expanded Phase I in pediatric patients with tenosynovial giant cell tumor, high risk Osteosarcoma, multiply recurrent malignancies in combination with other immunotherapy and Phase II focused on patients with NF1 and plexiform neurofibromas (PN) given a mast cell or other Kit mediated cell- cell crosstalk is thought to promote PN growth and possible progression to malignant peripheral nerve sheath tumors. We are also actively planning two new trials to target immune suppressive myeloid cells and stromal cell plasticity.

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，肿瘤和邻近的正常组织，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，以测量和表征循环骨髓来源的祖细胞，免疫，内皮和间质细胞，这些细胞可能在癌症和其他慢性疾病的情况下可能改变。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巨噬细胞以及基质细胞群体的CD4和CD8 T细胞。此外，我们测量了肿瘤细胞释放的微囊泡以及可能影响重要细胞行为的肿瘤造血细胞和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。我们最近的研究确定了宿主细胞的可塑性和细胞状态，确定了从这些细胞释放的微囊泡，而血管周细胞中的这种可塑性在调节转移中起关键作用。我们目前正在研究这种血管周细胞可塑性的标志物作为转移的预测指标，并对常规疗法和免疫基疗法的反应进行了预测。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（EWS）异种移植肿瘤细胞系和两个同步模型-Rhabdomyosarcoma（RMS）细胞系和一个骨肉瘤（OS）细胞系我们进行了流式细胞仪和免疫荧光，以证明髓细胞细胞和骨质细胞量的膨胀，以证明髓细胞细胞和替代层的细胞群体和较大的细胞群。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塑性的抑制剂专门评估对转移性进展的影响的抑制剂进行临床前研究。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。我们已经进行了串行的体内小鼠实验，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。我们正在使用不同的研究剂来确定它们对每个微环境细胞的特定影响。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细胞的良好窗口。我们的研究使用菌落刺激因子 - 一个受体（CSF1-R）抑制剂表明，这些RMS和EWINGS肉瘤模型分泌了大量CSF-1，并导致募集CSF-1R表达细胞。这些细胞在早期转移性部位发现，并具有免疫抑制性，可以保护散布的肿瘤细胞免受细胞毒性T细胞活性。我们正在开发促进基于髓样的抗肿瘤免疫和进行研究以确定这种细胞毒性的关键效应因子的方法。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基质细胞可塑性和功能的作用，并研究针对此过程的不同方法。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，以及促进转移的特定周围血管细胞群体的激活和扩展。今年，我们已经完成了pexidartinib的I期部分，该部分对FLT3，套件和CSF1R进行了侵害。现在，我们正在计划在患有心理巨型细胞肿瘤，高风险骨肉瘤，高风险骨肉瘤，与其他免疫疗法结合使用的多重复发性恶性肿瘤的小儿患者中入学，与其他免疫疗法相结合，并以NF1和其他细胞培养细胞的促进型细胞培养型细胞和其他型细胞形成型细胞，并促进了乳腺细胞的进展，并促进了乳突型细胞的进展。周围神经鞘肿瘤。我们还积极计划两项新试验，以靶向免疫抑制性髓样细胞和基质细胞可塑性。