RESUMEN
BACKGROUND: Rexinoids demonstrate anti-proliferative differentiation-inducing activity in multiple cancer types, including NSCLC. Prior studies have shown promising results when combining rexinoids with chemotherapy. This phase I/II study evaluates the tolerability and activity of a rexinoid, bexarotene, combined with weekly paclitaxel and monthly carboplatin. METHODS: Patients with confirmed advanced stage IIIB or IV NSCLC and adequate organ function were enrolled. They were scheduled to receive carboplatin (AUC =6) and 3 doses of weekly paclitaxel (100 mg/m2) every 4 weeks. Oral bexarotene was administered daily at two doses: 300 and 400 mg/m2/day. RESULTS: Thirty-three patients were enrolled. Fourteen received 300 mg/m2/day and 19 received 400 mg/m2/day of bexarotene. Hematologic toxicity included grade 3 neutropenia in 7 patients. Hyperlipidemia was a major non-hematologic toxicity which was medically managed. The recommended phase II dose of bexarotene was 400 mg/m2/day. Response rate was 35%. Median overall survival (OS) for all patients was 8.3 months with 1-year survival of 43%. Median OS for the 300 mg/m2 dose of bexarotene was 6.6 versus 9.8 months for the 400 mg/m2 dose (HR, 0.73; Log rank P=0.37). Patients who experienced hypertriglyceridemia had a median OS of 9.8 months compared to 4.9 months for those who did not (HR, 0.69; Log rank P=0.33). CONCLUSIONS: The 43% 1-year survival for patients receiving bexarotene with weekly paclitaxel and monthly carboplatin is encouraging. With the availability of new classes of agents for lung cancer, further evaluation of this regimen in unselected patients is not warranted. Our study confirms prior subgroup analyses showing a significant correlation between bexarotene-induced hypertriglyceridemia and survival. Further research is needed to identify molecular biomarkers to identify this subset of patients and to explore rexinoids in other combinations, especially with immunotherapy.
RESUMEN
BACKGROUND: Stromal-mediated signaling enhances NF-κB pathway activity in chronic lymphocytic leukemia (CLL) B cells, leading to cell survival and chemoresistance. Ubiquitination of IκBα may partially account for constitutive activation of NF-κB. MLN4924 is an investigational agent that inhibits the Nedd8-activating enzyme, thereby neutralizing Cullin-RING ubiquitin ligases and preventing degradation of their substrates. EXPERIMENTAL DESIGN: We conducted a preclinical assessment of MLN4924 in CLL. Primary CLL cells were cocultured in vitro with CD40L-expressing stroma to mimic the prosurvival conditions present in lymphoid tissue. The effect of MLN4924 on CLL cell apoptosis, NF-κB pathway activity, Bcl-2 family members, and cell cycle was assessed by flow cytometry, Western blotting, PCR, and immunocytochemistry. RESULTS: CD40L-expressing stroma protected CLL cells from spontaneous apoptosis and induced resistance to multiple drugs, accompanied by NF-κB activation and Bim repression. Treatment with MLN4924 induced CLL cell apoptosis and circumvented stroma-mediated resistance. This was accompanied by accumulation of phospho-IκBα, decreased nuclear translocation of p65 and p52 leading to inhibition of both the canonical and noncanonical NF-κB pathways, and reduced transcription of their target genes, notably chemokines. MLN4924 promoted induction of Bim and Noxa in the CLL cells leading to rebalancing of Bcl-2 family members toward the proapoptotic BH3-only proteins. siRNA-mediated knockdown of Bim or Noxa decreased sensitivity to MLN4924. MLN4924 enhanced the antitumor activity of the inhibitors of B-cell receptor (BCR)-associated kinases. CONCLUSIONS: MLN4924 disrupts NF-κB activation and induces Bim expression in CLL cells, thereby preventing stroma-mediated resistance. Our data provide rationale for further evaluation of MLN4924 in CLL.