Glioblastoma (GBM) is the most common and most aggressive brain tumor in humans. Because it is highly angiogenic, the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has now^ become the standard of care for treatment of recurrent GBM. We have found that vessel normalization and subsequent reduction of brain edema accounts for a major part of anti-VEGF treatment's benefit in GBM. However, this resulting benefit is modest and tumors inevitably progress and may even develop an increased invasive phenotype. To overcome this resistance, we aim to target two pathways that increase during escape from vessel normalization:
ANG2 (Aims 1 & 2) and SDFla/CXCR4 (Aim 3). Based on our prelinrdnary data, we hypothesize that anti-ANG2 therapy will increase the efficacy of anti-VEGF therapy by increasing the window of normalization and thereby sustainably decreasing edema (Aim 1). We also hypothesize that anti-VEGF and ANG2 combined therapy will polarize pro-tumor tumor-associated macrophages (TAMs) to anti-tumor TAMs and thus increase tumor response and mouse survival (Aim 2). Lastly, CXCR4-blockade can reduce infiltration and activation of immtmosuppressive (Gr-1+) BMDCs in non-CNS tumors, and preliminary evidence shows that SDFIa can reduce GBM invasion caused by anti-VEGF treatment. Thus, we now propose to use both genetic and pharmacologic approaches to test the role SDFla/CXCR4-blockade in improving the outcome of anti-VEGF therapy (Aim 3). TTie proposed work will reveal the molecular, cellular and physiological mechanisms of action of anti-Ang-2 and anti-SDF1alpha/CXCR4 agents in GBM - alone and with anti-VEGF agents, and inform the planned clinical trials with these agents in GBM patients.

Public Health Relevance

We propose a comprehensive approach to dissect the mechanisms of GBM escape from anti-VEGF therapy. We will examine two distinct pathways of evasion that emerged from our preclinical and clinical studies in GBM. Our research will generate important and translatable results for new combination therapy paradigms that are desperately needed for this dreadful disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
4P01CA080124-15
Application #
9057974
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
15
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
Ramjiawan, Rakesh R; Griffioen, Arjan W; Duda, Dan G (2017) Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy? Angiogenesis 20:185-204
Jung, Keehoon; Heishi, Takahiro; Khan, Omar F et al. (2017) Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy. J Clin Invest 127:3039-3051
Chen, Yunching; Liu, Ya-Chi; Sung, Yun-Chieh et al. (2017) Overcoming sorafenib evasion in hepatocellular carcinoma using CXCR4-targeted nanoparticles to co-deliver MEK-inhibitors. Sci Rep 7:44123
Aoki, Shuichi; Cobbold, Mark; Zhu, Andrew X et al. (2017) Can smart nanomedicine deliver effective targeted cytotoxic treatments to hepatocellular carcinomas while reducing the liver damage? Hepatology :
Mitchell, Michael J; Jain, Rakesh K; Langer, Robert (2017) Engineering and physical sciences in oncology: challenges and opportunities. Nat Rev Cancer 17:659-675
Kalpathy-Cramer, Jayashree; Chandra, Vyshak; Da, Xiao et al. (2017) Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma. J Neurooncol 131:603-610
Menter, Alex R; Carroll, Nikki M; Sakoda, Lori C et al. (2017) Effect of Angiotensin System Inhibitors on Survival in Patients Receiving Chemotherapy for Advanced Non-Small-Cell Lung Cancer. Clin Lung Cancer 18:189-197.e3
Li, Suyan; Kumar T, Peeyush; Joshee, Sampada et al. (2017) Endothelial cell-derived GABA signaling modulates neuronal migration and postnatal behavior. Cell Res :
Naxerova, Kamila; Reiter, Johannes G; Brachtel, Elena et al. (2017) Origins of lymphatic and distant metastases in human colorectal cancer. Science 357:55-60
Rowlands, Christopher J; Park, Demian; Bruns, Oliver T et al. (2017) Wide-field three-photon excitation in biological samples. Light Sci Appl 6:e16255

Showing the most recent 10 out of 271 publications