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: 8175364
• 负责人: Rosandra Kaplan
• 金额: $ 1.31万
• 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/8175364
• 关键词: Adult; Aging; Aging-Related Process; Angiogenic Factor; Area; Biological Assay; Biological Markers; Blood Circulation; Blood Vessels; Bone Marrow; Cardiovascular system; 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; 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; 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.

肿瘤基质是与肿瘤相互作用并交换信息的所有非肿瘤和宿主微环境细胞。传统上，重点是肿瘤细胞和所有特定的遗传失调。然而，越来越多的证据表明，这些宿主细胞在微环境中既有局部细胞又是从骨髓或远处招募到肿瘤的宿主细胞在肿瘤生长和进展以及对治疗的反应中起着至关重要的作用。我们将测量和表征肿瘤基质细胞以及其他在癌症和其他慢性疾病中可能改变的关键宿主细胞。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。与恶性肿瘤患者相比，这些细胞的变化将通过评估DNA的变化（包括表观遗传学变化以及包括microRNAS以及长期非编码RNA和蛋白质组学方法）的RNA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有关，可能有助于解释宿主细胞中响应癌症或多种慢性疾病的可逆变化。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。特别是，有助于形成新血管的未成熟细胞的内皮祖细胞可以用来帮助预测给定的治疗是靶向血管生成的，还是通过损害其制造新血管的能力来改变这些细胞的功能。同样，造血祖细胞可以有助于形成新的血管，因此还需要测量以评估抗血管生成疗法的功效，而两者组合可能是必不可少的，对于靶向一条途径和扩展另一种途径而发生的补偿至关重要。表达血管内皮生长因子受体One（VEGFR1）的造血祖细胞在癌症进展过程中在这些细胞上都上调，在这些细胞上都上调了在当前研究中可能进展的可能疾病进展的可能标记。 此外，肿瘤和非肿瘤细胞之间的清晰描述可能会模糊，因为潜在募集的骨髓衍生的细胞可能会获取遗传突变，并在此过程中成为生长肿瘤的一部分。对这些宿主细胞中发生的遗传变化的分析对于确定该募集是否解释了肿瘤中观察到的巨大细胞异质性，并可以解释治疗耐药性的出现。 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在生长和衰老过程中整个寿命中发生的变化。 我们将对骨髓，循环和特定组织部位的这些宿主骨髓祖细胞进行系统的比较，包括人儿科肿瘤，转移性或复发性肿瘤以及附近的正常组织。从这些研究中闪闪发光的信息将帮助我们学习如何根据疾病进展而根据需要改变治疗。 对这些基质细胞内发生的病理变化的更完整理解也可能与了解这些细胞在伤口愈合以及在发育和衰老中发生的变化中的作用有关。 我们将与多个临床财团合作，建立针对新型抗血管生成疗法的临床试验，包括诗歌（小儿肿瘤学实验性治疗研究联盟）和COG（临床肿瘤学组）。 此外，在上述翻译研究中发现的新型药物可有效靶向肿瘤基质，包括针对VEGFR1途径的肿瘤基质，将被带入针对儿科恶性肿瘤患者的临床试验。这些研究可以补充当前的传统疗法，并可能有效地治疗肿瘤进展。