Microarray Analysis Verifies Two Distinct Phenotypes of Glioblastomas Resistant to Antiangiogenic Therapy

Abstract

Purpose To identify mechanisms and mediators of resistance to anti-angiogenic therapy in human glioblastoma. Experimental Design We performed microarray gene expression analysis and immunohistochemistry comparing 21 recurrent glioblastomas progressing during anti-angiogenic treatment with VEGF neutralizing antibody bevacizumab to paired pre-treatment tumors from the same patients. Results Microarray analysis revealed that bevacizumab-resistant glioblastomas (BRGs) had 2 clustering patterns defining subtypes that reflect radiographic growth patterns. Enhancing BRGs (EBRGs) exhibited MRI enhancement, a long-established criterion for glioblastoma progression, and expressed mitogen-activated protein kinases, neural cell adhesion molecule-1 (NCAM-1), and aquaporin 4. Compared to their paired pre-treatment tumors, EBRGs had unchanged vascularity and hypoxia, with increased proliferation. Non-enhancing BRGs (NBRGs) exhibited minimal MRI enhancement but had FLAIR-bright expansion, a newer criterion for glioblastoma recurrence since the advent of anti-angiogenic therapy, and expressed integrin α5, laminin, fibronectin1, and PDGFRβ. NBRGs had less vascularity, more hypoxia, and unchanged proliferation than their paired pre-treatment tumors. Primary NBRG cells exhibited more stellate morphology with a 3-fold increased shape factor and were nearly 4-fold more invasive in matrigel chambers than primary cells form EBRGs or bevacizumab-naïve glioblastomas (P<0.05). Conclusion Using microarray analysis, we found two resistance patterns during anti-angiogenic therapy with distinct molecular profiles and radiographic growth patterns. These studies provide valuable biologic insight into the resistance that has limited anti-angiogenic therapy to date.

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

“…Data are in line with those we obtained recently in a cohort of patient biopsies indicating that α5 integrin mRNA level is high in p53wt tumors 8 (Figure 7b) that expression of phosphoPEA-15 and PEA-15 is related to the expression of α5 integrin in both cell lines. Thus, data suggested that under conditions where α5 integrin is highly expressed (in recurrent tumors, for example, DeLay et al 37 ), PEA-15 may be considered as an anti-apoptotic factor. Based on these results, we questioned the pertinence of PEA-15 and survivin as targets for pro-apoptotic signaling in other glioma cell lines.…”

Engineered knottin peptide enables noninvasive optical imaging of intracranial medulloblastoma

“…Additionally, EETI 2.5F binds to a broad range of tumor-associated integrin receptors, including α 5 β 1 integrin, which appears to be a critical factor for MB targeting. Brain tumors other than MB also display α v β 3 , α v β 5, or α 5 β 1 integrins; for example, recent evidence suggests that α 5 β 1 integrin plays an important role in drug-resistant and aggressive glioblastoma (13,16). High levels of at least one of these three integrin subtypes have also been found in a variety of tumors including melanoma; glioma; non-small-cell lung cancer; ovarian cancer; and tumors of the prostate, pancreas, cervix, and breast (18).…”

“…Specifically, α v β 3 , α v β 5 , and α 5 β 1 integrins have been shown to play critical roles in tumor survival, invasion, metastasis, and angiogenesis (12)(13)(14)(15)(16)(17) and are present at high levels in a variety of cancers (reviewed in ref. 18).…”

GLUT3 upregulation promotes metabolic reprogramming associated with antiangiogenic therapy resistance

“…Half of glioblastomas treated with bevacizumab acquire therapeutic resistance after an initial response (2). Acquired resistance to antiangiogenic therapy creates tumors we have found to have a poor prognosis (3,4), owing to these resistant tumors exhibiting both increased invasiveness and increased proliferation (3), making it a significant problem and preventing these treatments from fulfilling their therapeutic promise.…”