Craf1 ISIS 5132

Other attractive targets for antisense therapy in oncology are raf kinases and ras. Raf kinases are serine/threonine kinases that regulate mitotic signaling pathways, most notably the mitogen-activated protein kinase pathway that transmits signals from ras. c-raf has been reported to bind to bcl-2 and to be involved in the regulation of apoptosis. The ras oncogene is dysregulated or mutated more frequently than any other oncogene studied in human cancer (26,27). In several tumors, including breast and NSCLC, the expression of ras is a prognostic factor (28). In pancreatic cancer for which standard therapy is strikingly ineffective, 95% of all cases show ras mutations (27). This suggests that alterations in this pathway play a significant role in the pathogenesis of cancer (7).

An AS-ODN directed to the 3' untranslated region of the c-raf mRNA (ISIS 5132) inhibited the growth of human tumor cell lines in vitro and in vivo in association with specific downregulation of target message expression. In a phase I trial, changes in c-raf-1 mRNA expression were analyzed in peripheral blood mononuclear cells (PBMCs) collected from patients with advanced cancers treated with ISIS 5132. Significant reductions of c-raf-1 expression from baseline were detected in 13 of 14 patients (p = 0.002). Two patients, both of whom had demonstrated tumor progression with previous cytotoxic chemotherapy, exhibited long-term stable disease in response to the AS-ODN therapy. The investigators suggested that PBMCs can be used to confirm antisense-mediated inhibition of the target protein in vivo (29). However, one must consider that the decrease in c-raf-1 expression in total PBMCs could represent changes in the proportion of leukocyte populations owing to non-antisense-mediated immune stimulation and thus is not proof of an antisense-specific effect.

In a phase I trial, 31 patients with advanced malignancies received ISIS 5132 as a 2-h iv infusion three times weekly for three consecutive weeks with doses ranging from 0.5-6.0 mg/kg (30). Clinical toxicities included fever and fatigue, neither of which were dose limiting. Two patients experienced prolonged disease stabilization for more than 7 mo. In both of these cases, this was associated with reduction in c-raf-1 expression in PBMCs.

Cunningham et al. (31) reported the results of a trial testing continuous iv infusion of ISIS 5132 for 21 d every 4 wk in 34 patients with a variety of solid tumors refractory to standard therapy. Toxicities up to 4.0 mg/kg were not dose limiting. Doses of 2.0-4.0 mg/kg are comparable with doses in mice at which activity was observed in human xenograft models. Grade 3 fever occurred in 2 of the 34 patients treated. One patient treated with 5.0 mg/kg had fever as a dose-limiting toxicity. Three grade 3 or 4 thrombocytopenia and one grade 3 leukopenia were observed. Two patients developed sepsis: one of them, while septic, manifested grade 4 thrombocytopenia, grade 4 hyperbilirubinemia, and a grade 3 elevation in aspartate aminotransferase; the other developed grade 4 thrombocytopenia. Leukopenia was mild, and no patient had neutropenia. One patient with therapy refractory ovarian cancer had a dramatic reduction in her CA-125 level (97%), and two other patients had prolonged disease stabilization for 9 and 10 mo, respectively.

Rudin et al. (32) reported phase I results of ISIS 5132 administered as a weekly 24-h iv infusion in 22 patients with advanced cancer. The trial defined a maximum tolerated dose of 24 mg/kg/wk on this schedule. No major responses were documented. In contrast to other trials of ISIS 5132, there was no consistent suppression of PBMC c-raf-1 mRNA level, possibly suggesting that the efficacy and toxicity profile of AS-ODNs are dependent on the schedule of administration (32).

After the safety of ISIS 5132 was demonstrated in these phase I trials, several phase II trials were initiated. There was no evidence of single agent activity of ISIS 5132 in pretreated patients with recurrent ovarian cancer (33). In this study, 22 patients were treated at a dose of 4 mg/kg/d by 21-d continuous intravenous infusion every 4 wk. ISIS 5132 was well tolerated with no grade 3 or 4 hematological or biochemical toxicity. There were six documented episodes of grade 3 nonhematological toxicity (two cases of lethargy, one of anorexia, two of pain, and one of shortness of breath). No objective clinical response was seen. Three patients had stable disease for a median of 3.8 mo, and the remaining evaluable patients had documented progressive disease. No patient had a decrease in CA-125 of 50% or more.

No objective responses were seen in a phase II trial for patients with lung cancer (34). Twenty-two patients with progressive lung cancer (18 with NSCLC, 4 with SCLC) were treated with ISIS 5132 at 2 mg/kg/d, 21-d continuous infusion every 4 wk. Hematological toxicity did not exceed grade 2. Nonhematological toxicity was mild to moderate. Progressive disease was diagnosed in 10 patients, and 8 more patients were considered as treatment failures. No objective response was observed. Other phase II clinical studies including prostate and colon cancer are under way. Thus, there appears to be no clinical activity of ISIS 5132 as a single agent in these phase II trials.

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