Abstract 74: Establishment and characterization of the new sacral chordoma cell line Chor-IN-1

Abstract

Chordomas are rare, slowly growing but locally invasive bone tumors, derived from notocord remnants and characterized by the expression of “Brachyury” transcription factor. No standard medical therapy is available for this indication that is resistant to chemotherapy. Surgery associated to radiation, is the conventional treatment, but recurrence is extremely common and disease progression is severely crippling for patients. Expression of activated tyrosine kinase receptors and downstream pathways has been observed, including PDGFRβ and EGFR. Although some clinical responses have been obtained with Imatinib, also in combination with Sirolimus, and with Erlotinib, these treatments cannot eradicate the disease, and there is a strong need for new effective therapies. Only a handful of chordoma cell lines are available today and the paucity of in vitro models has so far limited the identification of new molecular targets and the assessment of the efficacy of small molecules inhibitors on chordoma cells proliferation. Here we present the establishment and the characterization of the new Chor-IN-1 chordoma cell line from a recurrent sacral tumor of a patient previously treated with Imatinib and radiotherapy. The cell line has a very slow growth rate, as normally observed for this type of tumors, and displays the typical chordoma physaliferous morphology. The karyotype is indicative of a single population and the Short Tandem Repeat (STR) profile is unique and 100% identical to that of the original tumor sample. The cell line expresses the most relevant chordoma biomarkers, like the product of the “T” gene Brachyury, CD24 and Cytoketatin 19. The non synonymous rs2305089 polymorphism in the “T” gene, associated with chordoma predisposition, was identified in the Chor-IN-1, as well as in the UCH-1 and UCH-2 chordoma reference cell lines. To further characterize the new cell line, its genetic background and transcriptional profile, with particular focus on kinases, was analysed by a Next Generation Sequencing (NGS) approach, in parallel with UCH-1 and UCH-2, to identify common and unique cancer related features. Finally, the cell line was characterized for its sensitivity to selected kinase inhibitor drugs already approved or in clinical testing, in parallel with the control cell lines. Among the several EGFR inhibitors tested, Afatinib resulted generally the most active, suggesting that treatment with this drug may represent a valuable therapeutic approach in chordoma. In conclusion, we report the establishment and in depth characterization of a new chordoma cell line that, retaining all the typical features of chordomas, represents a useful tool for the identification of candidate new druggable targets, or active drugs for chordoma therapy. Citation Format: Paola Magnaghi, Roberta Bosotti, Nadia Amboldi, Liviana Cozzi, Alessio Somaschini, Silvia Stacchiotti, Fabio Bozzi, Elena Tamborini, Elena Conca, Silvana Pilotti, Marco A. Pierotti, Sebastiano Di Bella, Carlo Cusi, Dario Ballinari, Arturo Galvani, Barbara Salom, Antonella Isacchi. Establishment and characterization of the new sacral chordoma cell line Chor-IN-1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 74. doi:10.1158/1538-7445.AM2015-74

Selinexor inhibits growth of patient derived chordomas in vivo as a single agent and in combination with abemaciclib through diverse mechanisms

“…Specific to the CF466 sacral chordoma model, TGFA was among the most significantly reduced genes, which is notable because it encodes an EGFR ligand, and SINE compounds are effective against cancer cells with engineered resistance to EGFR-tyrosine kinase inhibitors (64). Notably, direct EGFR inhibitors have shown promise as anti-cancer agents in chordoma and are being clinically evaluated (65). Our findings demonstrate clinical stage XPO1 inhibitors may be effective agents for treatment of effectiveness when combined with the CDK4/6 inhibitor abemaciclib.…”

Research hotspots and trends of chordoma: A bibliometric analysis

“…Imatinib, an inhibitor of PDGFR, was used in six patients with advanced chordoma, and patients' prognoses were improved with more than 1 year follow-up (32). Gefitinib and afatinib, EGFR inhibitors, were also effective in chordoma patients (33,34). With the treatment of apatinib, a potent inhibitor of VEGFR, one in seven patients achieved objective response according to RECIST and Choi criteria in 27 advanced chordoma patients (9).…”

Proteomics and phosphoproteomics of chordoma biopsies reveal alterations in multiple pathways and aberrant kinases activities

“…Not all PDGFR-positive chordomas paitients are sensitive to imatinib and it did not achieve dimensional and long-lasting responses as well (18,19). Although the European multi-center clinical trial involving afatinib is still ongoing, it is well established that single-afatinib therapies have not yielded lasting effects and the tumoral evolutions lead to the drug resistance (20,21). Besides, machine learning together with synergistic drug combinations have also been proposed in chordoma (22).…”