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.