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Chordomas are rare bone tumors with no approved therapy. These tumors express several activated tyrosine kinase receptors, which prompted attempts to treat patients with tyrosine kinase inhibitors. Although clinical benefit was observed in phase II clinical trials with imatinib and sorafenib, and sporadically also with EGFR inhibitors, therapies evaluated to date have shown modest activity. With the goal of identifying new drugs with immediate therapeutic potential for chordoma patients, we collected clinically approved drugs and other advanced inhibitors of MET, PDGFRβ, and EGFR tyrosine kinases, and assessed their antiproliferative activity against a panel of chordoma cell lines. Chordoma cell lines were not responsive to MET and PDGFRβ inhibitors. U-CH1 and UM-Chor1 were sensitive to all EGFR inhibitors, whereas the remaining cell lines were generally insensitive to these drugs. Afatinib was the only EGFR inhibitor with activity across the chordoma panel. We then investigated the molecular mechanisms behind the responses observed and found that the antiproliferative IC 50 s correlate with the unique ability of afatinib to promote degradation of EGFR and brachyury, an embryonic transcription factor considered a key driver of chordoma. Afatinib displayed potent antitumor efficacy in U-CH1, SF8894, CF322, and CF365 chordoma tumor models in vivo In the panel analyzed, high EGFR phosphorylation and low AXL and STK33 expression correlated with higher sensitivity to afatinib and deserve further investigation as potential biomarkers of response. These data support the use of afatinib in clinical trials and provide the rationale for the upcoming European phase II study on afatinib in advanced chordoma. Mol Cancer Ther; 17(3); 603-13. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Chordomas are rare and indolent bone tumors that arise in the skull base and mobile spine. Distant metastases occur in >20% of cases, but morbidity and mortality are mainly related to local relapses that affect the majority of patients. Standard chemotherapy has modest activity, whereas new targeted therapies (alone or in combination) have some activity in controlling disease progression. However, the scarcity of preclinical models capable of testing in vivo responses to these therapies hampers the development of new medical strategies., Methods: In this study, 8 chordoma samples taken from 8 patients were implanted in nude mice. Four engrafted successfully and gave rise to tumor masses that were analyzed histologically, by means of fluorescence in situ hybridization and biochemical techniques. The data relating to each of the mouse tumors were compared with those obtained from the corresponding human tumor., Results: All 4 engraftments retained the histological, genetic and biochemical features of the human tumors they came from. In one epidermal growth factor receptor(EGFR)-positive xenograft, responsiveness to lapatinib was evaluated by comparing the pre- and post treatment findings. The treatment induced a low-level, heterogeneous switching off of EGFR and its downstream signaling effectors., Conclusions: Overall, this model is very close to human chordoma and represents a new means of undertaking preclinical investigations and developing tailored therapies.

Background: To report on a prospective, investigator-driven, phase II study on lapatinib in epidermal growth factor receptor (EGFR)-positive advanced chordoma patients., Patients and Methods: From December 2009 to January 2012, 18 advanced progressing chordoma patients entered this study (median age: 61 years; disease extent: metastatic 72% and locally advanced 28%). Epidermal growth factor receptor (EGFR) expression and activation were evaluated by immunohistochemistry and/or phospho-arrays, real-time polimerase chain reaction, fluorescence immunostaining. Fluorescence in situ hybridization analysis was also carried out. Patients received lapatinib 1500 mg/day (mean dose intensity = 1282 mg/day), until progression or toxicity. The primary study end point was response rate (RR) as per Choi criteria. Secondary end points were RR by Response Evaluation Criteria in Solid Tumor (RECIST), overall survival, progression-free survival (PFS) and clinical benefit rate (CBR; RECIST complete response + partial response (PR) + stable disease (SD) ≥ 6 months)., Results: All patients were evaluable for response. Six (33.3%) patients had PR and 7 (38.9%) SD, as their best Choi responses, corresponding to RECIST SD in all cases. Median PFS by Choi was 6 [interquartile (IQ) range 3-8] months. Median PFS by RECIST was 8 (IQ range 4-12) months, with a 22% CBR., Conclusions: This phase II study showed a modest antitumor activity of lapatinib in chordoma. The clinical exploitation of EGFR targeting in chordoma needs to be further investigated, both clinically and preclinically. Clinical trial Registration No: EU Clinical Trials Register trial no. 2009-014456-29.

Background: The Ewing sarcoma family of tumors (ESFT) is one of the most common malignant neoplasms of children and adolescents, characterized by nonrandom translocations involving the Ewing sarcoma (EWS) gene. Over the years the adoption of intensive multimodality treatment approaches has led to a gradual improvement in the survival of patients with ESFT. The prognosis is still unsatisfactory for high-risk patients, however, and novel therapeutic approaches are desirable. The aim of the study was to investigate the expression/activation of KIT, PDGFRalpha, and PDGFRbeta receptor tyrosine kinases (RTKs) as potential therapeutic targets in ESFT., Methods: RNA and proteins were extracted from 20 frozen ESFT specimens to ascertain the state activation of KIT, PDGFRalpha, and PDGFRbeta., Results: No mutations were found, whereas the cognate ligands were detected in all cases by polymerase chain reaction (PCR). The expression and activation of KIT, PDGFRalpha, and PDGFRbeta were confirmed by quantitative PCR, immunohistochemistry, and immunoprecipitation and/or Western blot analysis. In particular, when compared with a protein pool obtained from normal adult tissues, PDGFRbeta showed a greater protein expression and/or a stronger phosphorylation signal., Conclusions: The results are consistent with an autocrine/paracrine loop activation of the KIT, PDGFRalpha, and PDGFRbeta receptors and suggest a rationale for the use of RTK inhibitors, either alone or in combination with chemotherapy.

Aims and Background: The treatment applied in our Institution to children with localized osteosarcoma between 1991 and 1999 consisted of four interleukin 2 (IL-2) courses (9 x 10(6) IU/mL/daily x 4), alternated with pre- and post-operative polichemotherapy. The aims of the present study were to quantify the modifications of some immunological parameters induced by IL-2 and to verify whether polychemotherapy could reduce them. An additional aim was to assess whether any correlation between the immune modifications and the clinical outcome could be found., Patients and Methods: We evaluated in 18 consecutive patients the following changes, induced in blood by each IL-2 course: number of lymphocyte subpopulations and natural killer (NK) cells, lymphokine activated killer (LAK) and NK activities., Results: Chemotherapy did not influence the modifications of the number of NK and CD4+ cells and of the LAK and NK activities, induced by each of the four courses of IL-2. The magnitudo of the NK activity and the peak of the NK absolute counts significantly correlated with the clinical outcome., Conclusions: The results show that the use of IL-2 permitted a repeated immune activation despite the intensive chemotherapy. Furthermore, although the limited number of cases precludes any definitive conclusion, the results suggest a possible role of the NK cells in the control of osteosarcoma.