At present survival from malignant glioblastoma (GBM, brain tumor) is usually less than a year. GBM are characterized by release of vascular endothelial growth factor (VEGF), an important regulator and promoter of new vessel formation (angiogenesis) and vascular permeability. Because of initial positive responses noted in clinical trials, it was thought that anti-angiogenic therapy targeting VEGF or VEGF receptors (VEGFRs) would become an effective tool for controlling GBM. However, it is now well recognized that the positive responses are temporary and that the tumors develop resistance and eventually progress, and in some cases with a more aggressive and invasive phenotype. To overcome the failure, it is essential to understand the basic mechanism of resistance to anti-angiogenic therapy. We hypothesize that anti-angiogenic treatment using VEGFR inhibitors (such as vetanalib) will cause hypoxia due to vascular loss and decreased endothelial cell (EC) survival, which will enhance compensatory increases in other pro-angiogenic factors such as stromal-cell derived factor 1 (SDF-1). SDF-1 in turn will induce the mobilization, migration and accumulation of endothelial progenitor cells (EPCs) around or into the tumor. Bone marrow (BM) derived precursor cells are known to promote angiogenesis and pro-growth responses and may be a mechanism for resistance. However it is not known whether EPCs accumulate in the tumor during anti VEGF therapy, or whether decreasing BM cells or neutralizing SDF-1 helps overcome resistance to anti- angiogenic therapy. It would be advantageous to use novel compounds that target multiple sites of angiogenesis to overcome anti-angiogenic resistance. HET0016 is one of the compounds that target multiple sites of angiogenesis. In this proposal we'll make orthotopic human glioma tumor model in nude rat. Tumor bearing animals will be treated either with vetanalib, or HET0016 alone or in combination. Dynamic contrast enhanced MRI (DCE-MRI) will be performed to determine permeability transfer constant (Ktrans), distribution (tumor blood) volume, tumor volume, enhancement pattern, and diffusion parameters in the tumors under basal and treated conditions. Western blot and RT-PCR analysis will determine the expression level of different angiogenic factors/receptors while immunohistochemistry will assess the vascular density and morphology. We expect that treatment resistance tumor will show changes in size, permeability, tumor blood volume, and other MRI parameters. The data may give direct evidence of compensatory/refractory angiogenesis, explain why certain tumors become refractory to anti VEGFR therapy and identify HET0016 as a possible adjuvant therapy in surmounting the tumor resistance to anti-angiogenic therapy. Previous studies by our group showed that transplanted EPCs migrated and incorporated in the tumor angiogenesis due to chemotactic cytokines released from the tumors (such as HIF-1 mediated SDF-1 release). To determine whether decreasing available BM cells or blocking accessible SDF-1, will diminish or even overcome resistance to anti VEGFR or HET0016 therapy. We will use sub lethal irradiation to lower the ability of the BM to release pro-angiogenic cells. In a set of experiments we will also block SDF-1 using specific antibodies or CXCR4 antagonists and thus reduce the ability of EPCs to migrate to the tumor. The initial migration and incorporation of intravenously administered EPCs will be detected by SPECT using In-111 labeled cells and the long term incorporation of the administered cells will be detected by cellular MRI using magnetically labeled cells. These data will be validated by immunohistochemistry. We expect the results of this experimental proposal will shade lights on the mechanisms of resistance to anti- angiogenic treatments and allow clinician to change the strategy of future treatment for GBM or other solid tumors.

Public Health Relevance

It is likely that multiple mechanisms can be brought into play in different tumors to explain evasive and intrinsic resistance to anti-angiogenic therapy. Mobilization and homing of monocytic progenitor cells to the tumor, which contribute to vasculogenesis and release multiple angiogenic and growth factors, may be an important contributor to this resistance. The use of accurate and sensitive non-invasive techniques to document changes in the tumor in the context of anti-angiogenic therapy and EPC's involvement represent a novel aspect. The use of cell labeling will allow to track cells non-invasively, an approach that might be possible to apply in a clinical setting. The use of a new agent, HET0016, in addition to vetanalib (PTK787), to get around the resistance to anti-angiogenic therapy is, we believe, innovative. Even a partial beneficial response would be highly relevant.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA160216-05
Application #
8997986
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Zhang, Huiming
Project Start
2012-03-19
Project End
2017-02-28
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Georgia Regents University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Angara, Kartik; Borin, Thaiz F; Rashid, Mohammad H et al. (2018) CXCR2-Expressing Tumor Cells Drive Vascular Mimicry in Antiangiogenic Therapy-Resistant Glioblastoma. Neoplasia 20:1070-1082
Johnson, Benjamin W; Achyut, Bhagelu R; Fulzele, Sadanand et al. (2018) Delineating Pro-Angiogenic Myeloid Cells in Cancer Therapy. Int J Mol Sci 19:
Arbab, Ali S; Rashid, Mohammad H; Angara, Kartik et al. (2017) Major Challenges and Potential Microenvironment-Targeted Therapies in Glioblastoma. Int J Mol Sci 18:
Sierra, Rosa A; Trillo-Tinoco, Jimena; Mohamed, Eslam et al. (2017) Anti-Jagged Immunotherapy Inhibits MDSCs and Overcomes Tumor-Induced Tolerance. Cancer Res 77:5628-5638
Zhang, Liyong; Wang, Yan; Rashid, Mohammad H et al. (2017) Malignant pericytes expressing GT198 give rise to tumor cells through angiogenesis. Oncotarget :
Jain, Meenu; Gamage, Nipuni-Dhanesha H; Alsulami, Meshal et al. (2017) Intravenous Formulation of HET0016 Decreased Human Glioblastoma Growth and Implicated Survival Benefit in Rat Xenograft Models. Sci Rep 7:41809
Iqbal, Sakib; Rashid, Mohammad H; Arbab, Ali S et al. (2017) Encapsulation of Anticancer Drugs (5-Fluorouracil and Paclitaxel) into Polycaprolactone (PCL) Nanofibers and In Vitro Testing for Sustained and Targeted Therapy. J Biomed Nanotechnol 13:355-366
Borin, Thaiz F; Angara, Kartik; Rashid, Mohammad H et al. (2017) Arachidonic Acid Metabolite as a Novel Therapeutic Target in Breast Cancer Metastasis. Int J Mol Sci 18:
Ouzounova, Maria; Lee, Eunmi; Piranlioglu, Raziye et al. (2017) Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade. Nat Commun 8:14979
Borin, Thaiz F; Shankar, Adarsh; Angara, Kartik et al. (2017) HET0016 decreases lung metastasis from breast cancer in immune-competent mouse model. PLoS One 12:e0178830

Showing the most recent 10 out of 45 publications