A phase II trial evaluating the effects and intra-tumoral penetration of bortezomib in patients with recurrent malignant gliomas.
One resistance mechanism in malignant gliomas (MG) involves nuclear factor-κB (NF-κB) activation. Bortezomib prevents proteasomal degradation of NF-κB inhibitor α (NFKBIA), an endogenous regulator of NF-κB signaling, thereby limiting the effects of NF-κB on tumor survival and resistance. A presurgical phase II trial of bortezomib in recurrent MG was performed to determine drug concentration in tumor tissue and effects on NFKBIA. Patients were enrolled after signing an IRB approved informed consent. Treatment was bortezomib 1.7 mg/m(2) IV on days 1, 4 and 8 and then surgery on day 8 or 9. Post-operatively, treatment was Temozolomide (TMZ) 75 mg/m(2) PO on days 1-7 and 14-21 and bortezomib 1.7 mg/m(2) on days 7 and 21 [1 cycle was (1) month]. Ten patients were enrolled (8 M and 2 F) with 9 having surgery. Median age and KPS were 50 (42-64) and 90 % (70-100). The median cycles post-operatively was 2 (0-4). The trial was stopped as no patient had a PFS-6. All patients are deceased. Paired plasma and tumor bortezomib concentration measurements revealed higher drug concentrations in tumor than in plasma; NFKBIA protein levels were similar in drug-treated vs. drug-naïve tumor specimens. Nuclear 20S proteasome was less in postoperative samples. Postoperative treatment with TMZ and bortezomib did not show clinical activity. Bortezomib appears to sequester in tumor but pharmacological effects on NFKBIA were not seen, possibly obscured due to downregulation of NFKBIA during tumor progression. Changes in nuclear 20S could be marker of bortezomib effect on tumor.
Department of Neurology, Northwestern University, Abbott Hall, Room 1123, 710 N. Lake Shore Dr., Chicago, IL, 60611, USA. jraizer@nmff.org.
Jeffrey J
JJ
Raizer
Department of Neurosurgery, Northwestern University, Chicago, IL, USA.
James P
JP
Chandler
Department of Neurosurgery, Neurocenter and Comprehensive Cancer Center, University of Freiburg, Freiburg, Germany.
Roberto
R
Ferrarese
Cadence Health Care-Central DuPage Hospital, Winfield, IL, USA.
Sean A
SA
Grimm
Marcus Neuroscience Institute, Boca Raton, FL, USA.
Robert M
RM
Levy
Illinois Masonic Hospital, Chicago, IL, USA.
Kenji
K
Muro
Department of Neurosurgery, Northwestern University, Chicago, IL, USA.
Joshua
J
Rosenow
Department of Preventive Medicine, Northwestern University, Chicago, IL, USA.
Irene
I
Helenowski
Department of Preventive Medicine, Northwestern University, Chicago, IL, USA.
Alfred
A
Rademaker
Millennium Pharmaceuticals, Inc, Cambridge, MA, UK.
Martin
M
Paton
Department of Radiation Oncology and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
Markus
M
Bredel
D000328:Adult; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000069286:Bortezomib / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D000077204:Temozolomide; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D000069286:Bortezomib; D003606:Dacarbazine; D046988:Proteasome Endopeptidase Complex; D000077204:Temozolomide
Bortezomib; Malignant glioma; Nuclear factor-κB; Temozolomide