Anti-Angiogenic Therapies in the Management of Glioblastoma

Jessica D. Schulte; Manish K. Aghi; Jennie W. Taylor


Chin Clin Oncol. 2021;10(4):37 

In This Article

Pathways of Resistance

Despite the biologic rationale and early promise of anti-angiogenic therapies, no agent in isolation or in combination has yet demonstrated an improvement in survival in GBM. Mechanisms of resistance are multifactorial and involve (I) upregulation of VEGF-independent angiogenesis; alternative methods of vasculogenesis including (II) recruitment of bone marrow-derived progenitors, (III) vascular mimicry and (IV) vessel co-option; (V) tumor cell autophagy; and (VI) tumor cell migration away from the tumor center and invasion into surrounding brain tissue (Figure 1). In addition to these pathways, there is some data that tumors treated with TKIs may acquire mutations in tyrosine kinase domain that dampen the response to TKIs, as seen with EGFR inhibitors gefitinib and erlotinib.[90]

Figure 1.

Mechanisms of resistance to anti-VEGF therapy. Resistance to VEGF targeted therapy is multifactorial, involving initial non-responsiveness of tumor cells to anti-VEGF therapy, as well as later acquired resistance via several mechanisms. [1] Upregulation of angiogenesis through VEGF-independent pathways, including FGF, PlGF, HGF, c-MET, ANG1, ANG2, and interleukins. [2] Increased recruitment of bone-marrow derived progenitors, including mesenchymal stem cells and endothelial progenitor cells, which differentiate into pericytes and endothelial cells, respectively, to populate new blood vessels. [3] Tumor cells under hypoxic stress sequester damaged cell components, in a process called "autophagy", which delays cellular apoptosis. [4] Tumor cells treated with anti-angiogenic agents migrate and invade away from hypoxic areas, making treatment with surgery and radiation more difficult. [5] Tumor cells in hypoxic environments will migrate toward blood vessels in the nearby normal brain, and "co-opt" these vessels for their supply of oxygen and nutrients. [6] Tumor cells can change their shape to resemble endothelial cells, and will aggregate with normal endothelial cells to create cylindrical structures with lumen, which behave as blood vessels. Adapted from Chandra et al. (89). ANG1/2, angiopoietin 1/2; bFGF, basic fibroblast growth factor; BNIP3, B-cell CLL/lymphoma 2 (BCL2)-interacting protein 3; c-MET, c-MET proto-oncogene; HIF-1α, hypoxia inducible factor 1 subunit alpha; HGF, hepatic growth factor; IL-8, interleukin-8; PDGF, platelet-derived growth factor; PlGF, placental growth factor; VEGF, vascular endothelial growth factor; MMP, matrix metalloproteinase; VE-cadherin, vascular endothelial cadherin.

Downregulation of VEGF leads to upregulation of other proangiogenic pathways, including PDGF, FGF, phosphatidylinositol glycan anchor biosynthesis class F (PlGF), hepatic growth factor (HGF)/c-MET protooncogene, ANG1, ANG2, delta4-notch (DLL4-Notch), and interleukins.[12,91,92] Hypoxia resulting from treatment with VEGF inhibitors upregulates HIF-1α, which in turn increases expression of ANG2.[93]FGF, which is involved in developmental and oncologic angiogenesis, may mediate resistance to VEGF inhibitors such as cediranib.[94,95] In addition to regulation of FGF and ephrin signaling pathways, the DLL4-Notch pathway may also mediate resistance to VEGF inhibition by stabilization of larger vessels.[96]

Blockade of VEGF/VEGFR signaling drives compensatory mechanisms of tumor vasculogenesis. Increased vascular co-option was seen in HIF-1α transgenic knockout mice, as well as GBM mouse xenograft models treated with a neutralizing VEGF antibody.[10,97] In humans, co-option was observed in resected tumor samples after pre-surgery exposure to bevacizumab or cediranib.[98,99] VEGF/VEGFR blockade also leads to de novo blood vessel formation and stabilization via the VEGF-independent pathways described above.[10,99–106]

Independent of increasing angiogenesis, disease resistance to anti-angiogenic agents may be mediated by other mechanisms of tumor perseverance. The hypoxia-induced pathways above also drive tumor progression through expansion of a HIF-regulated tumor progenitor population.[107] Tumor cells under hypoxic stress may also evade immediate cell death with autophagy-driven sequestering of damaged cell components, mediated by HIF-1α and B-cell CLL/lymphoma 2 (BCL2)-interacting protein 3 (BNIP3).[100] In addition to in situ resilience, tumor cells treated with anti-angiogenic agents migrate and invade away from hypoxic areas, demonstrated both in mouse models of GBM[108,109] and in humans.[110,111] This invasion is often perivascular in nature along blood vessels remaining after anti-angiogenic treatment, with tumor cells co-opting pre-existing vessels in a VEGF-independent manner.[97] This invasion is seen on MRI as non-enhancing disease and can be multifocal and thus more difficult to address with focal treatments (surgery, radiation, etc.) at the time of recurrence.[26,101,108] This invasive phenotype may be mediated through upregulation of genes that facilitate cellular motility as well as proteins that allow invasion of cells through the extracellular matrix including MMPs -2, -9, and -12; and secreted protein acidic and rich in cysteine (SPARC).[112] Among other pro-migratory mechanisms, tumor cells may transition to a mesenchymal phenotype mediated via PDGF and HGF-dependent MET signalling.[105,113] This was demonstrated after exposure to either bevacizumab or cediranib,[99,114] and led to interest in targeting the MET pathway in conjunction with VEGF manipulation, as MET may also contribute to tumor growth. Although a phase II trial evaluating bevacizumab with or without onartuzumab, a monovalent MET inhibitor, failed to improve PFS or OS,[115] trials of other c-MET inhibitors are in progress (NCT02386826, NCT02270034).