Mitchell Slater

Background:  Glioblastoma (GBM) is the most aggressive and vascularized primary brain tumor in adults, characterized by rapid growth, diffuse infiltration, and poor prognosis. Median survival remains under 15 months despite surgical resection, radiotherapy, and chemotherapy. A defining feature of GBM is its abnormal vasculature, driven by overexpression of vascular endothelial growth factor (VEGF). While VEGF-targeted agents like bevacizumab transiently normalize vessels and reduce edema, they do not significantly prolong overall survival due to the tumor’s ability to adapt. GBM compensates for VEGF inhibition by activating parallel pro-angiogenic pathways such as platelet-derived growth factor (PDGF), Apelin, thrombospondin-1 (THBS1), and TMEM230.¹⁻⁵ These mechanisms contribute to therapy resistance through vascular mimicry, endothelial-mesenchymal transition (EndMT), and immunosuppressive remodeling of the tumor microenvironment.³⁻⁵ As a result, single-pathway therapies are insufficient. A more comprehensive approach targeting multiple regulators of angiogenesis may offer greater therapeutic efficacy and durability. This literature review examines emerging strategies that combine gene editing and nanoparticle-based delivery platforms to overcome GBM’s adaptive angiogenic escape mechanisms.

Objective:  To evaluate the molecular drivers of resistance to anti-angiogenic therapy in GBM and assess novel multi-pathway and gene-editing approaches that enhance therapeutic outcomes through improved targeting, delivery, and tumor vascular disruption.

Search Methods:  A literature search was conducted using PubMed to identify peer-reviewed mechanistic studies published between 2017 and 2024. Keywords and MeSH terms included: “glioblastoma,” “angiogenesis,” “VEGF resistance,” “STAT3,” “Apelin,” “PDGF,” “THBS1,” “TMEM230,” and “nanoparticle delivery.” Five high-quality, primary research articles were selected based on relevance, methodology, use of in vivo models, and mechanistic insights.

Results:  Using similar animal models, Frisch et al. concluded that Apelin regulates endothelial tip cell behavior and is essential for tumor vascularization.¹ In contrast, Liu et al. demonstrated that PDGF signaling drives EndMT, suppressing VEGFR2 expression and reducing responsiveness to bevacizumab, whereas dual PDGF and VEGF inhibition restored sensitivity.³ Daubon and colleagues found that THBS1 promotes angiogenesis and invasion through CD47 and TGFβ signaling; silencing it improved bevacizumab response.⁴ Similarly, Cocola et al. showed that TMEM230 knockdown suppressed VEGF and Ang-2 expression, disrupting vascular mimicry.⁵ To build on these findings, Zhang et al. designed nanoparticles to deliver Cas9 targeting STAT3, achieving over 60% gene knockout and significantly reducing VEGF levels and tumor growth.²

Conclusion:  This review underscores the multifactorial nature of angiogenesis in GBM and the limitations of VEGF monotherapy. Multi-pathway inhibition targeting STAT3², PDGF³, THBS1⁴, and TMEM230⁵ shows strong potential for disrupting tumor vascular support systems and overcoming treatment resistance. Emerging strategies like CRISPR-based gene editing and targeted nanoparticle delivery offer improved precision, minimize off-target effects, and enhance blood-brain barrier penetration. Future therapies will likely require integrated approaches that combine molecular targeting, durable delivery platforms, and real-time biomarker monitoring to optimize outcomes for patients with GBM.

Works Cited

1. Frisch A, Kälin S, Monk R, Radke J, Heppner FL, Kälin RE. Apelin controls angiogenesis-dependent glioblastoma growth. Int J Mol Sci. 2020;21(11):3911.
2. Zhang H, Jiang W, Song T, et al. Lipid-polymer nanoparticles mediate compartmentalized delivery of Cas9 and sgRNA for glioblastoma vasculature and immune reprogramming. Adv Sci (Weinh). 2024;11(32):e2308931.
3. Liu T, Ma W, Xu H, et al. PDGF-mediated mesenchymal transformation renders endothelial resistance to anti-VEGF treatment in glioblastoma. Nat Commun. 2018;9(1):3439.
4. Daubon T, Léon C, Clarke K, et al. Deciphering the complex role of thrombospondin-1 in glioblastoma development. Nat Commun. 2019;10(1):1146.
5. Cocola C, Abeni E, Martino V, et al. Transmembrane protein TMEM230, regulator of glial cell vascular mimicry and endothelial cell angiogenesis in high-grade heterogeneous infiltrating gliomas and glioblastoma. Int J Mol Sci. 2024;25(7):3967.