BACKGROUND: Imatinib (IM) is active in advanced chordoma. The evidence of upstream and/or downstream mammalian target of rapamycin (mTOR) pathway activation prompted us to combine an mTOR inhibitor, sirolimus, to IM in IM-resistant advanced chordoma. PATIENTS AND METHODS: Since July 2007, 10 progressive advanced chordoma patients with secondary resistance to IM, and biochemical and/or immunohistochemical evidence of upstream and/or downstream mTOR effector activation, started IM (400 mg/day) plus sirolimus (2 mg/day) on a named basis. RESULTS: The mean treatment duration was 9 months. Of nine patients assessable for response, at 3 months, we had one RECIST partial response (PR), seven stable disease (SD) and one progressive disease (PD). According to Choi criteria applied even to magnetic resonance imaging, we had seven PR (> or =10% decrease in size in four cases), one SD and one PD. Seven patients had a positron emission tomography response. The clinical benefit [RECIST complete response + PR + SD > or =6 months] was 89%. Pretreatment mTOR effectors analysis carried out in nine cases was positive in all patients (AKT activation in six patients, S6Sp6 expression/activation in seven). Post-treatment biopsy in one responsive patient confirmed S6 switch off. CONCLUSION: In addition to PDGFRB, mTOR pathway can be activated in chordomas and the combination of IM plus rapalogs may be effective in IM-resistant chordomas.
BACKGROUND:Imatinib (IM) is active in advanced chordoma. The evidence of upstream and/or downstream mammalian target of rapamycin (mTOR) pathway activation prompted us to combine an mTOR inhibitor, sirolimus, to IM in IM-resistant advanced chordoma. PATIENTS AND METHODS: Since July 2007, 10 progressive advanced chordomapatients with secondary resistance to IM, and biochemical and/or immunohistochemical evidence of upstream and/or downstream mTOR effector activation, started IM (400 mg/day) plus sirolimus (2 mg/day) on a named basis. RESULTS: The mean treatment duration was 9 months. Of nine patients assessable for response, at 3 months, we had one RECIST partial response (PR), seven stable disease (SD) and one progressive disease (PD). According to Choi criteria applied even to magnetic resonance imaging, we had seven PR (> or =10% decrease in size in four cases), one SD and one PD. Seven patients had a positron emission tomography response. The clinical benefit [RECIST complete response + PR + SD > or =6 months] was 89%. Pretreatment mTOR effectors analysis carried out in nine cases was positive in all patients (AKT activation in six patients, S6Sp6 expression/activation in seven). Post-treatment biopsy in one responsive patient confirmed S6 switch off. CONCLUSION: In addition to PDGFRB, mTOR pathway can be activated in chordomas and the combination of IM plus rapalogs may be effective in IM-resistant chordomas.
Authors: Nathan A Dahl; Timothy Luebbert; Michele Loi; Ilana Neuberger; Michael H Handler; Bette Kay Kleinschmidt-DeMasters; Jean M Mulcahy Levy Journal: J Neuropathol Exp Neurol Date: 2017-06-01 Impact factor: 3.685
Authors: Christopher R Heery; B Harpreet Singh; Myrna Rauckhorst; Jennifer L Marté; Renee N Donahue; Italia Grenga; Timothy C Rodell; William Dahut; Philip M Arlen; Ravi A Madan; Jeffrey Schlom; James L Gulley Journal: Cancer Immunol Res Date: 2015-06-30 Impact factor: 11.151
Authors: Jason M Davies; Aaron E Robinson; Cynthia Cowdrey; Praveen V Mummaneni; Gregory S Ducker; Kevan M Shokat; Andrew Bollen; Byron Hann; Joanna J Phillips Journal: J Neurosurg Date: 2013-11-29 Impact factor: 5.115