Effects of bortezomib (PS-341) on NF-κB activation in peripheral blood mononuclear cells (PBMCs) of advanced non-small lung cancer (NSCLC) patients: A phase II/pharmacodynamic trial

Abstract

7145 Background: The proteasome inhibitor PS-341 disrupts multiple pathways involved in malignant cell growth and survival including antiapoptotic signaling by the transcription factor NF-κB. Inihibition of proteasomal degradation of ubiquitinated IκB prevents activation of NF-κB and phosphorylation of its p65 (RelA) subunit. Previous human studies showed proteasome inhibition in whole blood to occur within 1 hour after PS-341 dose and return to near-baseline levels in 24 hours. Methods: 23 patients with advanced NSCLC (≤ 1 prior regimen) received 1.3–1.5 mg/m2 PS-341 as an IV bolus on days 1,4,8,11 every 21 days. PBMCs were collected on day 1 of cycle 1 pre-treatment and 0.5, 1, 4, 8, and 24 h post-treatment. Expression of p65 and phosphorylated-p65 (pp65) was examined by western blot analysis in a group of patients (n=12) with and without gr 3 toxicity. Results: There was 1 PR and 9 SD (lasting > 4 cycles in 5 pts) in 22 evaluable pts. Grade 3 toxicities included N/V (3 pts), sensory neuropathy (1 pt), constipation (2 pts), rash (1 pt), and thrombocytopenia (3 pts). Total p65 did not change in the toxicity cohort. The ratio of pp65/p65 was similarly unaffected across the entire group, but in patients who experienced gr 3 toxicity a significant decrease in pp65/p65 was noted beginning at 30 min, with nadir at 4 h and recovering at 24 h. The mean decrease was to 79±21% of control. Patients without gr 3 toxicity had no decrease in pp65/p65 ratio. The expression of NF-κB-regulated genes and the relationship of NF-κB effects in PBMCs to outcome is being studied. Conclusions: 1) Single-agent PS-341 was tolerable and displayed antitumor activity in pts with minimally-pretreated advanced NSCLC. 2) The effects of PS-341 on NF-κB in PBMCs showed a decrease in antiapoptotic signaling in the 24 h after dose, maximal at 4 h, only in pts who experienced gr 3 toxicity. 3) The time-course of signaling effects may have implications for the scheduling of PS-341 in combination with cytotoxic chemotherapy. No significant financial relationships to disclose.