Chordoma Foundation


Platelet-derived Growth Factor Receptors are receptor tyrosine kinases (RTKs). RTKs code for proteins on the surface of the cell that become activated when their ligands bind and dimerize. There are two types of PDGFR: PDGFRα and PDGFRβ.

Ligands: PDGFA, B, C, and D
Location: PDGFRα on Chromosome 4q12; PDGFRβ on Chromosome 5q33

Activation of PDGFRs leads to the phosphorylation of signaling proteins involved in downstream pathways related to cell proliferation and growth, including PI3k-Akt-mTOR, and RAS/ERK, and STAT.1 Hyperactivation of PDGFR and its effects on downstream pathways can contribute to oncogenesis.

PDGFR in Chordoma

Overexpression and activation of PDGFRβ is particularly common in chordoma, suggesting that PDGFRβ might be involved in the growth of chordoma tumors.2 A number of chordoma patients treated with drugs that aim to suppress the activation of PDGFRβ have responded favorably, leading researchers to initiate clinical trials exploring their use in a greater number of chordoma patients. This page contains a summary of published research exploring the role of PDGFR in chordoma and evaluating its inhibition as a method for treating the disease.

Molecular Evidence

Copy Number Variation

  • Chromosomal Aberrations: Chromosome 5 gains and losses have been observed in chordomas.3 4
  • Gene Copy Number Variation: PDGFRβ gene losses and polysomies have been detected in a number of chordomas.3 5

Somatic Mutation

No gain-of-function mutations have been found in PDGFRα or PDGFRβ, though a few silent mutations have been detected.4

Gene Expression

PDGFRβ expression is higher in chordomas than it is in synovial sarcoma controls, but expression is lower than that in normal tissues.4 PDGFRβ is also more highly expressed in chordoma than in the control tissue fetal nucleus pulposus.6 The gene’s ligand, PDGFB, has been expressed in all chordoma samples tested.7

Protein Expression

The PDGFRα and PDGFRβ proteins are expressed in nearly all chordoma samples tested.4 7 8 9 10 11 12 13 14 15 16 17 Expression level has been found to be significantly correlated to brachyury expression levels, suggesting PDGFRb might play a role in tumorigenesis.18 Expression of PDGRFa has also been found to be significantly correlated to EGFR and overall survival for patients with high PDGFRa expression was significantly worse at 10 years than those with low PDGFRa expression.14 Higher expression of PDGFRβ was found to be associated with poorer prognosis in clival chordoma.19

Protein Activation

p-PDGFRβ, the phosphorylated/active form of the PDGFRβ protein, is detected in virtually all chordomas studied.2 5 7 10 20 Studies report the co-activation of PDGFRβ with EGFR, suggesting there may be benefit to treatment approaches that inhibit the activation of both targets.20

Preclinical Evidence

In-vitro Efficacy

  • PDGFR Inhibition: Chordoma cell lines U-CH1 and U-CH2 exhibit greater response and attenuated invasion when exposed to a combination of HDAC and PDGFR inhibition. The same study found that PTEN deficient tumors showed greater resistance to PDGFR inhibition than those that were not PTEN deficient.21
  • Sunitinib, imatinib, crenolanib: Treatment of a panel of six chordoma cell lines with each of these PDGFR inhibitors did not result in anti-proliferative activity.17
  • PDGFRβ siRNA Knockdown: Knockdown of PDGFRβ via siRNA transfection in U-CH2 chordoma cells significantly reduced cell invasion and decreased protein expression of p-PDGFRβ, mTOR, and p-mTOR.19

Clinical Evidence

Case Reports and Case Series

  • Imatinib:
    • In 6 patients with PDGFRβ-expressing chordomas, subjective improvement was reported in 4/5 symptomatic patients. CT and MRI scans indicated overt tumor liquefaction and signs of anti-tumor activity after variable treatment time periods in the patients who were evaluable.2 Expansion of this study to 18 patients resulted in 11 patients (61%) with radiological signs of “tissue response”, 2 patients (11%) with a “dimensional response”, and 1 patient (6%) with a “functional response”.22
    • 7 pediatric patients were treated with 340 mg/m2/d and a partial metabolic response was observed in a clivus chordoma case after 1 month of treatment.15
    • A RECIST stabilization of the disease was the best response observed in 17 patients with PDGFRβ-expressing chordomas. Pain relief (with reduction in analgesics use) was obtained in 6/11 symptomatic patients.23
    • After progression on conventional chemotherapy, a patient was treated with a combination of carboplatin and imatinib mesylate and had remained stable for 5 years as of 2015.24
    • After treatment with neoadjuvant chemotherapy, cisplatin, and 800 mg imatinib mesylate, followed by local resection, a patient was put on adjuvant imatinib mesylate (800 mg) and maintained stable disease for 5 years.24
    • A patient with sacral chordoma was treated with 400mg imatinib for 16 months until control imaging showed the progression of disease.25
  • Imatinib and Erlotinib: 
    • A patient’s clival tumor progressed after 5 months treatment with Imatinib. Subsequent treatment with Erlotinib (an EGFR inhibitor) led to partial response of the tumor, which had been sustained for 28+ months as of July 2014.26
    • A patient with advanced, EGFR-expressing chordoma who had advanced on Imatinib responded to Erlotinib (an EGFR inhibitor) during 12 months of treatment.27
  • 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 pazopanib inhibits multiple RTKs including PDGFR and VEGFR.28
  • 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 PDGFR and VEGFR.28
    • A patient with clival chordoma was treated with 400mg imatinib for 25 months. When progressive disease was confirmed, imatinib was stopped and the patient was treated with 37.5mg sunitinib for 6 months.25
  • Pazopanib:
    • 3 patients were treated with the multi-targeted kinase inhibitor pazopanib 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.28
    • A patient with relapsed lumbar spine chordoma was treated with pazopanib, resulting in tumor reduction (−23.1% reduction in size) and prolonged disease control. 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.29
  • Sunitinib: A patient with clival chordoma being treated with 37.5mg sunitinib has reported stable disease at 20 months.25

Retrospective Studies

  • Imatinib: A retrospective series of 46 patients with progressive locally advanced or metastatic PDGFRB/PDGFB positive chordoma treated with 800mg/d imatinib observed stable disease (SD) in 34 (74%) of patients and progressive disease (PD) in 12 (26%). PET metabolic response was detected in 40% of the evaluated patients. Median progress free survival (PFS) was 9.9 months with 65% patients progression-free at 6 months and 21% of patients progression-free for more than 18 months. Median overall survival (OS) was 30 months.12
  • Imatinib, sorafenib, and sunitinib: A retrospective series of 80 patients found the median PFS was 7.2 months among 62 patients treated with imatinib, 19.2 months among a group of 13 patients treated sorafenib (n=11), sunitinib (n=1), and temsirolimus (n=1), and 14.7 months among 5 patients treated with erlotinib. There were no statistically significant differences between imatinib versus the group (sorafenib, sunitinib, and temsirolimus), erlotinib versus this group, or imatinib versus erlotinib.30

Phase I Trials

  • Imatinib + metronomic cyclophosphamide: Observed long-lasting stable disease in chordoma patients (median PFS=10.2 months; range, 4.2-18+).31
  • Nilotinib: 200mg Nilotinib per day with radiation therapy was found to be safe and tolerated in a Phase I trial of 23 patients with high-risk chordoma. The objective best response rate was 6% (1/18, 95% CI: 0.1-27%). The median PFS was 58.15 months (95% CI: 39.10-inf). The median OS was 61.5 months (43.1-inf) and the 2-year OS rate was 95%.32

Phase II Trials

  • Imatinib: ORR 2% (1/56 partial response), 9/56 minor response. Disease stabilization in 72% of cases (PR +SD); median PFS 9 months. 64% clinical benefit rate. 10/26 patients who had a PET at baseline achieved >=25% decrease in standard uptake value. Trend in mean pain intensity was consistent with radiologic response.10
  • Imatinib + Everolimus: 43 adults with progressive advanced chordoma treated with imatinib plus everolimus found limited antitumor activity (9 partial response, ORR 20.9%). However, a subgroup of patients with highly phosphorylated mTOR effectors were responsive, suggesting that activation of the mTOR pathway could be predictive of response to imatinib plus everolimus.33
  • 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%.34
  • Dasatinib:A multi‐institutional, open‐label, single‐arm trial of dasatinib (a PDGFRB inhibitor) in patients with advanced sarcoma included 32 chordoma patients. 6-month PFS was 54% and 5-year OS was 18%. 35 
  • 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.36

Di M, Kong E, Yip S, Rostomily R. Converging paths to progress for skull base chordoma: Review of current therapy and future molecular targets. Surg Neurol Int. 2013;4:72. [PubMed]
Casali P, Messina A, Stacchiotti S, et al. Imatinib mesylate in chordoma. Cancer. 2004;101(9):2086-2097. [PubMed]
Scheil S, Brüderlein S, Liehr T, et al. Genome-wide analysis of sixteen chordomas by comparative genomic hybridization and cytogenetics of the first human chordoma cell line, U-CH1. Genes Chromosomes Cancer. 2001;32(3):203-211. [PubMed]
Tamborini E, Miselli F, Negri T, et al. Molecular and biochemical analyses of platelet-derived growth factor receptor (PDGFR) B, PDGFRA, and KIT receptors in chordomas. Clin Cancer Res. 2006;12(23):6920-6928. [PubMed]
Dewaele B, Maggiani F, Floris G, et al. Frequent activation of EGFR in advanced chordomas. Clin Sarcoma Res. 2011;1(1):4. [PubMed]
Chen H, Zhang K, Lu J, Wu G, Yang H, Chen K. Comprehensive analysis of mRNA-lncRNA co-expression profile revealing crucial role of imprinted gene cluster DLK1-MEG3 in chordoma. Oncotarget. 2017;8(68):112623-112635. [PMC]
Tamborini E, Virdis E, Negri T, et al. Analysis of receptor tyrosine kinases (RTKs) and downstream pathways in chordomas. Neuro Oncol. 2010;12(8):776-789. [PubMed]
Fasig J, Dupont W, LaFleur B, Olson S, Cates J. Immunohistochemical analysis of receptor tyrosine kinase signal transduction activity in chordoma. Neuropathol Appl Neurobiol. 2008;34(1):95-104. [PubMed]
Orzan F, Terreni M, Longoni M, et al. Expression study of the target receptor tyrosine kinase of Imatinib mesylate in skull base chordomas. Oncol Rep. 2007;18(1):249-252. [PubMed]
Stacchiotti S, Longhi A, Ferraresi V, et al. Phase II study of imatinib in advanced chordoma. J Clin Oncol. 2012;30(9):914-920. [PubMed]
de C, Guimaraes G, Aguiar S, et al. Tyrosine kinase receptor expression in chordomas: phosphorylated AKT correlates inversely with outcome. Hum Pathol. 2013;44(9):1747-1755. [PubMed]
Hindi N, Casali P, Morosi C, et al. Imatinib in advanced chordoma: A retrospective case series analysis. Eur J Cancer. 2015;51(17):2609-2614. [PubMed]
Akhavan-Sigari R, Abili M, Gaab M, et al. Immunohistochemical expression of receptor tyrosine kinase PDGFR-α, c-Met, and EGFR in skull base chordoma. Neurosurg Rev. 2015;38(1):89-98; discussion 98-9. [PubMed]
Akhavan-Sigari R, Gaab M, Rohde V, Abili M, Ostertag H. Expression of PDGFR-α, EGFR and c-MET in spinal chordoma: a series of 52 patients. Anticancer Res. 2014;34(2):623-630. [PubMed]
Geoerger B, Morland B, Ndiaye A, et al. Target-driven exploratory study of imatinib mesylate in children with solid malignancies by the Innovative Therapies for Children with Cancer (ITCC) European Consortium. Eur J Cancer. 2009;45(13):2342-2351. [PubMed]
Bosotti R, Magnaghi P, Di B, et al. Establishment and genomic characterization of the new chordoma cell line Chor-IN-1. Sci Rep. 2017;7(1):9226. [PubMed]
Magnaghi P, Salom B, Cozzi L, et al. Afatinib is a new therapeutic approach in chordoma with a unique ability to target EGFR and Brachyury. Mol Cancer Ther. Published online December 13, 2017. [PubMed]
Zhai Y, Bai J, Gao H, et al. Clinical Features and Prognostic Factors of Children and Adolescents with Clival Chordomas. World Neurosurg. 2017;98:323-328. [PubMed]
Zhai Y, Bai J, Wang S, et al. Analysis of clinical factors and PDGFR-β in predicting prognosis of patients with clival chordoma. J Neurosurg. Published online January 5, 2018:1-9. [PubMed]
Stacchiotti S, Tamborini E, Lo V, et al. Phase II study on lapatinib in advanced EGFR-positive chordoma. Ann Oncol. 2013;24(7):1931-1936. [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]
Casali PG, Stacchiotti S, Messina A, et al. Imatinib mesylate in 18 advanced chordoma patients. Journal of Clinical Oncology [abstract]. Published June 2005. 10.1200/jco.2005.23.16_suppl.9012″ target=”_blank” rel=”noopener noreferrer”>
Ferraresi V, Nuzzo C, Zoccali C, et al. Chordoma: clinical characteristics, management and prognosis of a case series of 25 patients. BMC Cancer. 2010;10:22. [PubMed]
Rohatgi S, Ramaiya N, Jagannathan J, Howard S, Shinagare A, Krajewski K. Metastatic Chordoma: Report of the Two Cases and Review of the Literature. Eurasian J Med. 2015;47(2):151-154. [PubMed]
Alan O, Akin T, Ercelep O, et al. Chordoma: a case series and review of the literature. J Med Case Rep. 2018;12(1):239. [PubMed]
Houessinon A, Boone M, Constans J, Toussaint P, Chauffert B. Sustained response of a clivus chordoma to erlotinib after imatinib failure. Case Rep Oncol. 2015;8(1):25-29. [PubMed]
Launay S, Chetaille B, Medina F, et al. Efficacy of epidermal growth factor receptor targeting in advanced chordoma: case report and literature review. BMC Cancer. 2011;11:423. [PMC]
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. [PMC]
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
Lebellec L, Chauffert B, Blay J, et al. Advanced chordoma treated by first-line molecular targeted therapies: Outcomes and prognostic factors. A retrospective study of the French Sarcoma Group (GSF/GETO) and the Association des Neuro-Oncologues d’Expression Française (ANOCEF). Eur J Cancer. 2017;79:119-128. [PubMed]
Adenis A, Ray-Coquard I, Italiano A, et al. A dose-escalating phase I of imatinib mesylate with fixed dose of metronomic cyclophosphamide in targeted solid tumours. Br J Cancer. 2013;109(10):2574-2578. [PubMed]
Cote G, Barysauskas C, DeLaney T, et al. A Phase I Study of Nilotinib plus Radiation in High-Risk Chordoma. Int J Radiat Oncol Biol Phys. Published online August 2, 2018. [PubMed]
Stacchiotti S, Morosi C, Lo V, et al. Imatinib and Everolimus in Patients With Progressing Advanced Chordoma: A Phase 2 Clinical Study. Cancer. Published online September 14, 2018. [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]
Schuetze S, Bolejack V, Choy E, et al. Phase 2 study of dasatinib in patients with alveolar soft part sarcoma, chondrosarcoma, chordoma, epithelioid sarcoma, or solitary fibrous tumor. Cancer. 2017;123(1):90-97. [PubMed]
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]

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