Chordoma Foundation



Vascular Endothelial Growth Factor is a signaling protein that stimulates the formation of blood vessels. VEGF production is stimulated in hypoxic (low oxygen) environments. VEGF expression is mediated by HIF-1a expression under hypoxic conditions.1

Location: Chromosome 6p12

Overexpression of VEGF is a mediator of tumor angiogenesis (by which new blood vessels form from pre-existing ones). Since solid tumors cannot grow without a blood supply, VEGF expression allows tumors to develop and maintain the vasculature necessary for them to grow and metastasize.

VEGF in Chordoma

Deletions of the region of chromosome 6 where VEGF resides have been detected in primary chordomas, and VEGF expression levels are often high. A number of chordoma patients being treated with VEGF inhibitors have achieved stable disease after the addition of Bevacizumab, a drug that targets the VEGF pathway, to their treatment regimens. This page contains a summary of published research suggesting that VEGF is a target and evaluating its inhibition as a potential method of treating chordoma.

Molecular Evidence

Chromosomal Aberrations

  • Deletions of the region of chromosome 6 harboring the VEGF gene have been detected in 3/6 primary chordoma tested but only in 1/8 recurrent chordomas.2

Somatic Mutations

  • Point mutations were found within the coding sequence of the gene coding for the VEGFR protein (the oncogene KDR) in 2 of 9 chordoma samples studied by Fischer et al.3

Protein Expression

  • VEGF protein expression is detected, and levels are often high, in the majority of chordoma samples tested 1 4 5 6 7, including cases of pediatric chordoma.8
  • Recurrent cases showed higher VEGFR1 expression than primary cases and VEGF-A was significantly higher in cases with rapid progression compared to those with slow progression. Higher VEGFR1 and VEGFR2 expression were significantly associated with faster tumor growth.7
  • Expression of VEGF is reported to be activated by expression of HIF-1α, another possible therapeutic target in chordoma, and indeed, VEGF expression levels are significantly correlated with HIF-1α levels expression levels in chordoma samples.1
  • VEGFR2, the primary responder to VEGF binding, is variably expressed in chordoma tumors. A recent study by Akhavan-Sigari et al. found strong expression of VEGFR2 in 80/80 recurrent and 35/40 primary chordomas (and moderate expression in the remaining 5 primary tumors). Patients with high expression of VEGFR2 had significantly poorer 10-year survival than those with low expression. An earlier study Akhavan-Sigari et al. found no expression in 114/145 tumors, indicating that further work is necessary to clarify the VEGFR2 expression patterns in chordoma tumor samples.7 9 10

Protein Activation

  • RTK array in 12 chordomas revealed no activation of VEGF receptors.11

Preclinical Evidence

In vitro Efficacy

  • Cells cultured under hypoxic conditions expressed significantly more VEGF than cells cultured under normoxic conditions.12

In vivo Efficacy

  • Overexpression of EGFR and VEGFR2 (KDR) potently induced a chordoma phenotype in zebrafish, yet overexpression of Brachyury did not.13

Clinical Evidence

Case Reports

There have been a number of case reports publishing the results of treating chordoma patients with a therapeutic agent that targets VEGF.

  • Thalidomide: A patient with a sacral mass experienced an improvement in symptoms after 2 weeks at 100mg tumor regression was radiologically at 200 mg. Progression free 14 months. Thalidomide has been shown to inhibit VEGF secretion and cell migration and increase cell adhesion to collagen with a resultant inhibitory effect on blood vessel formation.14
  • Erlotinib + Cetuximab, followed by Erlotinib + Bevacizumab: A patient was treated with an unresected skull-based tumor was treated with Erlotinib and Cetuximab. When PET scan indicated no reduction in tumor methionine uptake, Cetuximab was replaced with Bevacizumab. Methionine uptake decreased and MRI revealed a clear reduction in contrast enhancement and a slight decrease in tumor size.15 Patient remains stable 4.5 years after Erlotinib/Bevacizumab treatment began. Another patient was treated with erlotinib and briefly with cetuximab. Her clival tumor was stable for 2 years stable on erlotinib alone. After patient progressed, bevacizumab was added to treatment regimen for 2 months and brought instant relief of neurological pain. Erlotinib treatment continued, and disease remains stable disease after 2 years.16
  • Erlotinib + Bevacizumab: A patient whose sacral tumor was proliferative was treated for 5 months until she developed a therapy-related infection. Tests revealed that proliferation had stopped. Disease remains stable 2.5 years after treatment.16
  • Sorafenib: A 57-year-old man with lumbar chordoma whose pre-treatment TSH levels were normal presented with hyperthyroidism and Graves’ disease after 18 weeks of treatment with 800 mg sorafenib.17
  • Pazopanib: In one study, three patients were treated with the multi-targeted kinase inhibitor panzopanib which targets VEGFR, PDGFR, and other RTKs. Two patients observed stable disease for 14 and 15 months, respectively, and one patient had progressive disease after 3 months.18 A fourth patient with relapsed lumbar spine chordoma was treated with pazopanib, resulting in tumor reduction (−23.1% reduction in size) and prolonged disease control. To note, this particular patient did not have positive brachyury staining and was found to have ATM Q2593 mutation, ARID1AS2149fs47 mutation, CDKN2A/B loss, EP300 L415P mutation (subclonal), and MLL3 Y306 mutation. INI-1/SMARCB1 was included in the panel and showed no mutations.19
  • Imatinib and pazopanib: One patient was treated with imatinib for 9 months and then pazopanib for 3 months and then discontinued due to progressive disease. The multi-targeted kinase inhibitor panzopanib inhibits multiple RTKs including VEGFR and PDGFR.18
  • Imatinib and sunitinib: One patient was treated with imatinib and then the multi-targeted kinase inhibitor sunitinib and observed a partial response and stabilization of disease for 27 months. The multi-targeted kinase inhibitor sunitinib inhibits multiple RTKs including VEGFR and PDGFR.18
  • Pazopanib: One patient was treated with crushed pazopanib for 2.5 years until evidence of disease progression.20

Phase II Trials

  • Sunitinib: 4/9 chordoma patients treated with this inhibitor of multiple RTKs achieved SD for at least 16 weeks. Qualitative decreases in tumor density were observed.21
  • Sorafenib: In an uncontrolled Phase II trial of 800 mg sorafenib (VEGFR 1,2,3 and PDGFRβ inhibitor), an Intent-to-treat best objective response was achieved in 1 of 27 cases. At 9 months, progression-free survival rate was 73.0%, and at 12 months overall survival rate was 86.5%.22
  • Sorafenib:In the Angionext Phase II trial (NCT 00874874), 26 patients were treated with 800 mg/day for 9 months. Progression-free survival rate (PFS) was 72.9%. Higher levels of VEGF expression were associated with poorer outcome, though the association was not significant.23
  • Apatinib: Two chordoma patients were included in a single-arm, nonrandomized Phase II trial of the VEGFR2 inhibitor apatinib.24

Li X, Ji Z, Ma Y, Qiu X, Fan Q, Ma B. Expression of hypoxia-inducible factor-1α, vascular endothelial growth factor and matrix metalloproteinase-2 in sacral chordomas. Oncol Lett. 2012;3(6):1268-1274. [PubMed]
Bayrakli F, Guney I, Kilic T, Ozek M, Pamir M. New candidate chromosomal regions for chordoma development. Surg Neurol. 2007;68(4):425-430; discussion 430. [PubMed]
Fischer C, Scheipl S, Zopf A, et al. Mutation Analysis of Nine Chordoma Specimens by Targeted Next-Generation Cancer Panel Sequencing. J Cancer. 2015;6(10):984-989. [PubMed]
Chen K, Yang H, Lu J, et al. Expression of vascular endothelial growth factor and matrix metalloproteinase-9 in sacral chordoma. J Neurooncol. 2011;101(3):357-363. [PubMed]
Deniz M, Kiliç T, Almaata I, Kurtkaya O, Sav A, Pamir M. Expression of growth factors and structural proteins in chordomas: basic fibroblast growth factor, transforming growth factor alpha, and fibronectin are correlated with recurrence. Neurosurgery. 2002;51(3):753-760; discussion 760. [PubMed]
Tauziéde-Espariat A, Bresson D, Polivka M, et al. Prognostic and Therapeutic Markers in Chordomas: A Study  of 287 Tumors. J Neuropathol Exp Neurol. 2016;75(2):111-120. [PubMed]
Morimoto Y, Tamura R, Ohara K, et al. Prognostic significance of VEGF receptors expression on the tumor cells in skull base chordoma. J Neurooncol. 2019;144(1):65-77.
Beccaria K, Tauziède-Espariat A, Monnien F, et al. Pediatric Chordomas: Results of a Multicentric Study of 40 Children and Proposal for a Histopathological Prognostic Grading System and New Therapeutic Strategies. J Neuropathol Exp Neurol. 2018;77(3):207-215.
Akhavan-Sigari R, Gaab M, Rohde V, et al. Expression of vascular endothelial growth factor receptor 2 (VEGFR-2), inducible nitric oxide synthase (iNOS), and Ki-M1P in skull base chordoma: a series of 145 tumors. Neurosurg Rev. 2014;37(1):79-88. [PubMed]
Akhavan-Sigari R, Gaab M, Rohde V, Abili M, Ostertag H. Prognostic significance of immunohistochemical expression of VEGFR2 and iNOS in spinal chordoma. Eur Spine J. 2014;23(11):2416-2422. [PubMed]
Dewaele B, Maggiani F, Floris G, et al. Frequent activation of EGFR in advanced chordomas. Clin Sarcoma Res. 2011;1(1):4. [PubMed]
Lee D, Zhang Y, Kassam A, et al. Combined PDGFR and HDAC Inhibition Overcomes PTEN Disruption in Chordoma. PLoS One. 2015;10(8):e0134426. [PubMed]
D’Agati G, Cabello E, Frontzek K, et al. Active receptor tyrosine kinases, but not Brachyury, are sufficient to trigger chordoma in zebrafish. Dis Model Mech. 2019;12(7).
Chay W, Teo M, Sittampalam K, Toh H. Effective use of thalidomide in the treatment of recurrent metastatic chordoma. J Clin Oncol. 2011;29(16):e477-80. [PubMed]
Asklund T, Danfors T, Henriksson R. PET response and tumor stabilization under erlotinib and bevacizumab treatment of an intracranial lesion non-invasively diagnosed as likely chordoma. Clin Neuropathol. 2011;30(5):242-246. [PubMed]
Asklund T, Sandström M, Shahidi S, Riklund K, Henriksson R. Durable stabilization of three chordoma cases by bevacizumab and erlotinib. Acta Oncol. 2014;53(7):980-984. [PubMed]
Eroukhmanoff J, Castinetti F, Penel N, Salas S. Auto-immune thyroid dysfunction induced by tyrosine kinase inhibitors in a patient with recurrent chordoma. BMC Cancer. 2016;16:679. [PubMed]
Lipplaa A, Dijkstra S, Gelderblom H. Efficacy of pazopanib and sunitinib in advanced axial chordoma: a single reference centre case series. Clin Sarcoma Res. 2016;6:19. [PubMed]
Ribeiro MFSA, de Sousa MC, Hanna SA, et al. Tumor Reduction with Pazopanib in a Patient with Recurrent Lumbar Chordoma. Case Reports in Oncological Medicine. 2018;2018:1-7. doi:10.1155/2018/4290131
Stein J, Milhem M, Vaena D. Clinical outcomes and toxicities of pazopanib administered orally in crushed form: Case reports and review of the literature. J Oncol Pharm Pract. April 2019:1078155219841108.
George S, Merriam P, Maki R, et al. Multicenter phase II trial of sunitinib in the treatment of nongastrointestinal stromal tumor sarcomas. J Clin Oncol. 2009;27(19):3154-3160. [PubMed]
Bompas E, Le C, Tresch-Bruneel E, et al. Sorafenib in patients with locally advanced and metastatic chordomas: a phase II trial of the French Sarcoma Group (GSF/GETO). Ann Oncol. 2015;26(10):2168-2173. [PubMed]
Lebellec L, Bertucci F, Tresch-Bruneel E, et al. Circulating vascular endothelial growth factor (VEGF) as predictive factor of progression-free survival in patients with advanced chordoma receiving sorafenib: an analysis from a phase II trial of the french sarcoma group (GSF/GETO). Oncotarget. 2016;7(45):73984-73994. [PubMed]
Liao Z, Li F, Zhang C, et al. Phase II trial of VEGFR2 inhibitor apatinib for metastatic sarcoma: focus on efficacy and safety. Exp Mol Med. 2019;51(3):24.

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