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: 8349478
• 负责人: Rosandra Kaplan
• 金额: $ 26.46万
• 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/8349478
• 关键词: Adult; Aging; Aging-Related Process; Angiogenic Factor; Area; Biological Assay; Biological Markers; Blood Circulation; Blood Vessels; Bone Marrow; Cell physiology; Cells; Childhood; Chronic Disease; Clinical; Clinical Oncology; Clinical Trials; Collaborations; Colony-Forming Units Assay; Complement; DNA; Development; Disease; Disease Progression; Disseminated Malignant Neoplasm; Distant; Effectiveness; Epigenetic Process; Financial compensation; Flow Cytometry; Functional RNA; Gene Mutation; Genetic; Growth; Growth and Development function; Heart Diseases; Hematopoietic; Hematopoietic stem cells; Heterogeneity; Human; Inflammatory; Investigation; Learning; Longevity; Longitudinal Studies; Malignant Neoplasms; Measures; Mediator of activation protein; Mesenchymal; MicroRNAs; Monitor; Mus; Mutation; Neoplasm Metastasis; Normal tissue morphology; Nutrient; Oncology Group; Organ Transplantation; Pathway interactions; Patients; Pediatric Neoplasm; Pediatric Oncology; Play; Population; Process; Prognostic Marker; Proteomics; RNA; Recruitment Activity; Recurrence; Recurrent tumor; Resistance; Risk; Role; Site; Stem cells; Stromal Cells; Testing; Therapeutic; Tissues; Translational Research; Vascular Diseases; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-1; Wound Healing; angiogenesis; base; bone circulation; improved; indexing; monocyte; neoplastic cell; novel; progenitor; prognostic; protein expression; receptor; response; therapeutic target; therapy design; tissue regeneration; tool; traditional therapy; translational study; tumor; tumor growth; tumor progression; tumorigenesis; tumorigenic

Tumor stroma is all the non-tumor recruited and host microenvironmental cells that are interacting with and exchanging information with the tumor. The focus traditionally has been on the tumor cell and all the genetic dysregulation specific to it. However, a growing body of evidence shows that these host cells both local cells within the microenvironment and those recruited from the bone marrow or distant sites to the tumor can play a crucial role in tumor growth and progression as well as response to therapy. We will measure and characterize the tumor stromal cells as well as other key host 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. The changes in these cells compared to patients with malignancy will be tested by assessment in changes in DNA including epigenetic changes as well as RNA including both microRNAs as well as long non-coding RNAs and proteomic approaches to demonstrate changes in protein expression. Both microRNAs and lincRNAs have been associated with developmental and tumorigenic processes and may help to explain reversible changes that occur in the host cells in response to cancer or a multitude of chronic diseases. The specific changes in these cells may help to serve as prognostic markers of disease progression as well as response to therapies. In particular, endothelial progenitor cells that are immature cells that help to form new blood vessels can be used to help predict if a given treatment is targeting angiogenesis or if it is altering the function of these cells by impairing their ability to make new blood vessels. Hematopoietic progenitor cells similarly can help to form new blood vessels and therefore also need to be measured to assess efficacy of antangiogenic therapies and the two in combination may be essential to see compensation that occurs with targeting one pathway and expansion of another. The hematopoietic progenitor cells that express vascular endothelial growth factor receptor one (VEGFR1) a receptor that is found on both endothelial and hematopoietic cells is upregulated on these cells during cancer progression and is being used as a possible marker for possible disease progression in current studies. Furthermore, clear delineation between tumor and non-tumor cells may blur as potentially recruited bone marrow-derived cells may acquire genetic mutations and in doing so become part of the growing tumor. Analysis of the genetic changes that occur in these host cells are necessary to determine if this recruitment explains the great cellular heterogeneity seen in tumors and may explain how treatment resistance arises. In addition, specific changes that occur in pro-angiogenic factors as well as these bone marrow-derived progenitor cells may be useful in elucidating changes that occur over the lifespan during growth and aging. We will perform a systematic comparison of these host bone marrow progenitor cells in the bone marrow, circulation and specific tissue sites including human pediatric tumors and metastatic or recurrent tumors as well as nearby normal tissue. Information gleamed from these studies will help us learn how to alter therapy as needed with disease progression. A more complete understanding of the pathological changes that occur within these stromal niche cells may also serve relevant to understanding the role of these cells in wound healing and in the changes that occur in development and aging. We will establish clinical trials focused on novel anti-angiogenic therapies in collaboration with several clinical consortiums including POETIC (Pediatric Oncology Experimental Therapeutic Investigation Consortium) group and COG (Clinical Oncology Group). Further, novel agents discovered in the translational studies described above that are effective in targeting the tumor stroma including those targeting specifically the VEGFR1 pathway will be taken into clinical trials for pediatric patients with malignancies. These studies can complement current traditional therapies and may prove effective in treatment of tumor progression.

肿瘤基质是所有非肿瘤募集的宿主微环境细胞，它们与肿瘤相互作用并交换信息。传统上，焦点一直集中在肿瘤细胞及其特有的所有遗传失调上。然而，越来越多的证据表明，这些宿主细胞（无论是微环境中的局部细胞还是从骨髓或远处部位招募到肿瘤的细胞）都可以在肿瘤生长和进展以及对治疗的反应中发挥至关重要的作用。我们将测量和表征肿瘤基质细胞以及在癌症和其他慢性疾病中可能发生改变的其他关键宿主细胞。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。与恶性肿瘤患者相比，这些细胞的变化将通过评估 DNA 变化（包括表观遗传变化）以及 RNA（包括 microRNA 和长非编码 RNA）以及蛋白质组学方法来测试，以证明蛋白质表达的变化。 microRNA 和 lincRNA 都与发育和致瘤过程相关，可能有助于解释宿主细胞响应癌症或多种慢性疾病而发生的可逆变化。这些细胞的特定变化可能有助于作为疾病进展以及治疗反应的预后标志物。特别是，内皮祖细胞是有助于形成新血管的不成熟细胞，可用于帮助预测给定的治疗是否针对血管生成，或者是否通过削弱这些细胞形成新血管的能力来改变这些细胞的功能。造血祖细胞同样可以帮助形成新血管，因此也需要进行测量以评估抗血管生成疗法的功效，并且将两者结合起来可能对于观察针对一种途径和另一种途径的扩张所发生的补偿至关重要。造血祖细胞表达血管内皮生长因子受体一 (VEGFR1)，这是一种在内皮细胞和造血细胞上都存在的受体，在癌症进展过程中这些细胞上的表达上调，并且在当前的研究中被用作可能的疾病进展的可能标志物。 此外，肿瘤细胞和非肿瘤细胞之间的清晰界限可能会变得模糊，因为潜在招募的骨髓来源细胞可能会发生基因突变，从而成为生长中的肿瘤的一部分。有必要对这些宿主细胞中发生的遗传变化进行分析，以确定这种募集是否可以解释肿瘤中观察到的巨大细胞异质性，并可以解释治疗耐药性是如何产生的。此外，促血管生成因子以及这些骨髓来源的祖细胞中发生的特定变化可能有助于阐明生命周期中生长和衰老过程中发生的变化。 我们将对骨髓、循环系统和特定组织部位（包括人类儿科肿瘤和转移性或复发性肿瘤以及附近正常组织）中的这些宿主骨髓祖细胞进行系统比较。从这些研究中获得的信息将帮助我们了解如何根据疾病进展的需要改变治疗方法。更全面地了解这些基质细胞内发生的病理变化也可能有助于了解这些细胞在伤口愈合以及发育和衰老过程中发生的变化中的作用。 我们将与包括 POETIC（儿科肿瘤实验治疗研究联盟）小组和 COG（临床肿瘤学小组）在内的多个临床联盟合作，建立专注于新型抗血管生成疗法的临床试验。此外，在上述转化研究中发现的可有效靶向肿瘤基质的新型药物，包括特异性靶向 VEGFR1 通路的药物，将被纳入针对患有恶性肿瘤的儿科患者的临床试验。这些研究可以补充当前的传统疗法，并可能证明对治疗肿瘤进展有效。