ZIA BC 011334 (ZIA) | |||
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Title | Biomarkers and Therapeutic Targets in Angiogenesis and Metastasis | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Kaplan, Rosandra | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $379,286 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Digestive Diseases (15.0%) Metastasis (100.0%) Childhood Cancers (100.0%) |
Brain (10.0%) Breast (10.0%) Childhood Leukemia (20.0%) Colon/Rectum (5.0%) Hodgkins disease (5.0%) Leukemia (20.0%) Lung (5.0%) Nervous System (20.0%) Neuroblastoma (10.0%) Non Hodgkins Lymphoma (5.0%) Pancreas (10.0%) Sarcoma (20.0%) |
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Research Type | |||
Technology and/or Marker Testing in a Clinical Setting Systemic Therapies - Discovery and Development |
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Abstract | |||
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 v |