Anti-Angiogenic Therapies in the Management of Glioblastoma

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

Chin Clin Oncol. 2021;10(4):37

Abstract and Introduction

Abstract

Angiogenesis is a central feature of glioblastoma (GBM), with contribution from several mechanisms and signaling pathways to produce an irregular, poorly constructed, and poorly connected tumor vasculature. Targeting angiogenesis has been efficacious for disease control in other cancers, and given the (I) highly vascularized environment in GBM and (II) correlation between glioma grade and prognosis, angiogenesis became a prime target of therapy in GBM as well. Here, we discuss the therapies developed to target these pathways including vascular endothelial growth factor (VEGF) signaling, mechanisms of tumor resistance to these drugs in the context of disease progression, and the evolving role of anti-angiogenic therapy in GBM.

Introduction

Glioblastoma (GBM) is the most aggressive and unfortunately most common, malignant primary brain tumor, with a median survival of 10–31 months depending on age at diagnosis, extent of resection, treatment and molecular prognostic factors.^[1–4] Angiogenesis is a central feature of GBM, with microvascular glomeruloid proliferation requisite for histological diagnosis.^[5,6] Endothelial cells comprise the tumor blood vessels, facilitating delivery of nutrients and oxygen. In addition, endothelial cells directly support glioma progenitor cell proliferation through intercellular signaling pathways, contributing to tumor growth and resilience.^[7]

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Next Section

Abstract and Introduction
Mechanisms of Angiogenesis
Therapeutic Strategies Targeting Angiogenesis
Pathways of Resistance
Evolving use of Anti-angiogenic Therapy
Conclusions
References

Table 1. Clinical trials with anti-angiogenic treatment
Drug	Target	Farthest trial design	Results
Antibodies
Andecaliximab (GS-5745)	MMP9	Phase II recurrent GBM	Ongoing (NCT03631836)
Bevacizumab	VEGF-A	Phase III newly diagnosed GBM	RT/TMZ ± BEV; AVAGlio: mOS 16.8 vs. 16.7 months; mPFS 8.4 vs. 4.3 months (43); RTOG 0825: mOS 15.7 vs. 16.1 months; mPFS 10.7 vs. 7.3 months (42)
Bevacizumab	VEGF-A	Phase III recurrent GBM	CCNU ± BEV—EORTC 26101; mOS 9.1 vs. 8.6 months; mPFS 4.2 vs. 1.5 months. Grade 3 to 5 adverse events 63.6% vs. 38.1% (41)
Carotuximab (TRC184)	Endoglin (CD105)	Phase II recurrent GBM	In combination with BEV, mPFS 1.8–2.9 months and mOS 5.75–10 months (53,54)
PF-04856884	Ang2	Phase I recurrent GBM	Terminated due to high toxicity (55)
Ramucirumab	VEGFR-2	Phase II recurrent GBM	PFS6 12.5%, mOS 11.4 months (clinicaltrials.org, NCT00895180)
Tanibirumab (TTAC-0001)	VEGFR-2	Phase II recurrent GBM	Ongoing (NCT03856099)
Tyrosine kinase inhibitor
AEE788	VEGFR-1/2, EGFR	Phase I recurrent GBM	Significant toxicity leading to discontinuation in 17% of patients (56)
Anlotinib	VEGFR-1/2/3, c-Kit, PDGFR-α, FGFR-1/2/3	Phase I/II newly diagnosed GBM	Ongoing (NCT04119674, NCT04157478)
Anlotinib	VEGFR-1/2/3, c-Kit, PDGFR-α, FGFR-1/2/3	Phase I/II recurrent GBM	Ongoing (NCT04004975)
Apatinib	VEGFR-2, c-Kit, c-Src	Phase II recurrent GBM	mPFS 6 months, mOS 9.3 months (57)
Axitinib	VEGFR-1/2/3	Phase II recurrent GBM	PFS6 26% as monotherapy or in combination with lomustine (58); GLIAVAS: PFS6 18% as monotherapy or in combination with PD-1 inhibitor avelumab (59)
Cabozantinib (XL184)	VEGFR-2,3, REF, c-kit, c-MET	Phase II newly diagnosed GBM	In patients naïve to anti-angiogenic therapy and those with prior exposure, respectively, mOS 10.4 and 4.6 months PFS6 27.8% and 8.5%, mPFS 3.7 and 2.3 months, Grade 3/4 toxicities 84.7% and 72.4% of patients (60,61)
Cediranib	VEGFR-1/2/3 PDGFR-α/β, c-kit	Phase III in recurrent GBM	No improvement over lomustine alone (49,62,63)
Cediranib	VEGFR-1/2/3 PDGFR-α/β, c-kit	Phase II in newly diagnosed GBM	Ongoing (NCT01062425)
Dovitinib	VEGFR-1/2/3, FGFR-1/2/3, PDGFR-β	Phase II recurrent GBM	mOS 3–7.9 months, PFS6 5% (64,65)
Enzastaurin	PKC-β PI3K/AKT	Phase III in recurrent GBM	Stopped at interim analysis due to no benefit compared to lomustine (mOS 6.6 months, mPFS 1.6 months) (50)
Enzastaurin	PKC-β PI3K/AKT	Phase II in newly diagnosed GBM	In combination with RT + TMZ, mOS 17.1 months, mPFS 8.31 months (66)
Lenvatinib (E7080)	VEGFR-2/3 FGFR1 PDGFR-β	Phase II recurrent GBM	mOS 4.11 months, PFS6 8.3%, mPFS 1.9 months (67)
Lenvatinib (E7080)	VEGFR-2/3 FGFR1 PDGFR-β	Phase II advanced solid tumors (including GBM)	Combined with pembrolizumab; ongoing (NCT03797326)
Nintedanib	VEGFR-1/2/3, FGFR1/2/3 and PDGFRα/β	Phase II recurrent GBM	mOS 6.9 months, PFS6 0% (68)
Pazopanib	VEGR-1/2/3 PDGFR- α/β c-kit	Phase I/II newly diagnosed GBM	Ongoing (NCT02331498)
		Phase II recurrent GBM	mOS 8.03 months, PFS6 3%, mPFS 2.77 months (69)
		Phase I/II recurrent GBM	Combined with lapatinib (HER2/neu, EGFR inhibitor), early termination due to PFS6 0% and 15% in EGFRvIII mutant and EGFR wildtype, respectively (70)
Ponatinib	VEGFR-2	Phase II in recurrent GBM	mOS 98 days, mPFS 28 days (71)
Regorafenib	VEGFR1/3, PDGFR-β, FGFR 1	Phase II in recurrent GBM	Ongoing (NCT04051606)
Sorafenib	VEGFR-2/3, PDGFR-β, FLT3, Raf kinase	Phase II newly diagnosed GBM	mOS 12 months, mPFS 6 months (72)
Sorafenib	VEGFR-2/3, PDGFR-β, FLT3, Raf kinase	Phase II in recurrent GBM	In combination with BEV, mOS 5.6 months, PFS6 20.4% (73); in combination with TMZ, mOS 41.5 weeks, PFS6 9.4%, mPFS 6.4 weeks (74); in combination with Temsirolimus in anti-VEGF naïve patients, mOS 6.3 months, PFS6 17.1%, mPFS 2.6 months (75); in combination with erlotinib, mOS 5.7 months, PFS6 14% mPFS 2.5 months (76)
Sunitinib	VEGFR-2, PDGFR-α/β, c-kit	Phase II in recurrent GBM	mOS 9.6–12.6 months, PFS6 12.5–21.5%, PFS 2.2 months, no improvement in combination with irinotecan (77,78)
Sunitinib	VEGFR-2, PDGFR-α/β, c-kit	Phase III in recurrent GBM	Ongoing (NCT02239952)
Tandutinib (MLN 518)	PDGFR, FLT3, c-kit	Phase II recurrent GBM	OS 8.8–11 months, PFS6 16–23%, PFS 1.9–4.1 months; increased toxicity compared to bevacizumab, no significant benefit of combination (79,80)
Tesevatinib	EGF, HER2, VEGF, ephrin B4	Phase II recurrent GBM	Ongoing (NCT02844439)
Tivozanib	VEGFR-2/3	Phase II recurrent GBM	mOS 8.1 months, mPFS 2.3 months (81)
Vandetanib	VEGFR-1/2, EGFR, RET	Phase II newly diagnosed GBM	mOS 16.6 months, PFS 7.7 months [addition of vandetanib not significantly improved compared to RT + TMZ alone (82)]
		Phase II recurrent anaplastic astrocytoma	Given after carboplatin, mOS 9.27 months, PFS6 17.4 months [worse PFS6 and OS when given concurrently with carboplatin (83)]
		Phase II recurrent GBM	mOS 5.6 months, mPFS 1.7 months; No added benefit with addition of vandetanib compared to carboplatin monotherapy (84)
Other
Aflibercept (VEGF-Trap)	IgG fused to receptor sequences of VEGFR-1,2	Phase II recurrent AA	mOS 39 weeks, PFS6 25%, mPFS 4 weeks (44)
Aflibercept (VEGF-Trap)	IgG fused to receptor sequences of VEGFR-1,2	Phase II GBM	mOS 55 weeks, PFS6 7.7%, mPFS 12 weeks (44)
Cilengitide	SMI to αvβ3, αvβ5, αvβ1 Integrins	Phase III in newly diagnosed GBM	mOS 26.3 months; no benefit of adding cilengitide to TMZ + RT alone (52)
Cilengitide	SMI to αvβ3, αvβ5, αvβ1 Integrins	Phase II in recurrent GBM	mOS 9.9 months, PFS6 15%, mPFS 8.1 weeks (85)
CT-322	Pegylated Adnectin binding VEGFR-2	Phase II recurrent GBM	Terminated due to inefficacy (86)
Macitentan	SMI to Endothelin-1A/B receptor	Phase I in newly diagnosed and recurrent GBM	Terminated due to poor accrual
PT2385	SMI to HIF-2alpha	Phase II recurrent GBM	mPFS 6.7 months (87)
RO5323441	PIGF inhibitor (binds to and activated VEGFR)	Phase I recurrent GBM	Increased serum concentration when combined with bevacizumab; brain concentration not studied (88)
Trebananib (AMG 386)	Ang-1/2 peptide-Fc fusion protein	Phase II recurrent GBM	In combination with bevacizumab, mOS 9.5 months, 6PFS 24.3%, mPFS 3.6 months (51)
VB-111	adenovirus with pre-pro-endothelin1 driving apoptotic receptor	Phase III recurrent GBM	Ongoing (NCT02511405)
VXM01	Oral vaccine against VEGFR-2	Phase II recurrent GBM	Ongoing (NCT03750071)

List of therapies targeted toward angiogenesis in GBM, the molecular target, highest available trial phase (phase I, II, and III) and brief summary of the results of these trials. For ongoing trials, the National Clinical Trials (NCT) registration number is provided. AA, anaplastic astrocytoma; Akt, AKT serine/threonine kinase 1; Ang2, angiopoietin-2; BEV, bevacizumab; CCNU, lomustine; EGF/EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; FLT3, Fms-like tyrosine kinase; GBM, glioblastoma multiforme; HER2, human epidermal growth factor receptor 2; MMP, matrix metalloprotease; PFS6, 6-month progression-free survival; mPFS, median progression-free survival; mOS, median overall survival; PDGFR, platelet derived growth factor receptor; PIK3, phosphatidylinositol-4,5-bisphosphate 3-kinase; PKC-β, protein kinase c beta HIF, hypoxia inducible factor; PKC, protein kinase C; PI3K, phosphatidylinositol 3-kinase; PlGF, placental derived growth factor; REF, Aly/REF exporter; RET, RET proto-oncogene; RT, radiation therapy; SMI, small molecular inhibitor; SRC, SRC proto-oncogene; TMZ, temozolomide; VEGFR, vascular endothelial growth factor receptor.