Response to imatinib plus sirolimus in advanced chordoma.
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.


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.


CONCLUSIONS
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.
Stacchiotti
S
S
Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. silvia.stacchiotti@istitutotumori.mi.it
Marrari
A
A
Tamborini
E
E
Palassini
E
E
Virdis
E
E
Messina
A
A
Crippa
F
F
Morosi
C
C
Gronchi
A
A
Pilotti
S
S
Casali
P G
PG
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D015153:Blotting, Western; D002817:Chordoma / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D051058:Oncogene Protein v-akt / Q000096:biosynthesis / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects; D012447:Sacrum / Q000473:pathology; D020123:Sirolimus / Q000008:administration & dosage* / Q000009:adverse effects; D019292:Skull Base Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013125:Spinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome; D055815:Young Adult
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D051058:Oncogene Protein v-akt; D020123:Sirolimus