Inhibitors Of The Downstream Pathways Ras signaling

Activation of the Ras signaling pathway is essential for BCR/ABL function. After BCR/ABL has activated Ras, Ras requires several additional posttranslational modifications, including prenylation. Prenylation involves adding a lipid anchor to the target protein, which facilitates binding of this protein to cellular membranes, allowing them to function as intermediates in the process(es) of signal transduction. In the Ras pathway, prenylation is catalyzed by farnesyl protein transferase; the farnesyl transferase inhibitors (FTIs) interfere with this step by inhibiting this enzyme. Given the central role that the ras oncogene plays in controlling cellular metabolism, multiple FTI compounds are currently being developed and tested across a wide range of hematologic malignancies. A phase I/II study of tipifarnib, an FTI, in patients with a spectrum of myeloproliferative disorders reported preliminary results in 23 patients.34 Tipifarnib was administered at a dose of 300 mg p.o. b.i.d. for 21 days every 4 weeks. Clinical WBC responses [normalization of WBC, complete remission (CR); or >50% WBC count reduction, partial remission] were seen in 5 of 21 (24%) evaluable patients. No cytogenetic responses were seen in six evaluable patients. Grade 2 anemia and greater than grade 3 thrombocytopenia were the most common hematologic toxicities.34 Two other phase I studies of tipifarnib in combination with imatinib for the treatment of CML have also been reported. Cortes et al. conducted a phase I study of the combination of tip-ifarnib with imatinib in patients with CML in chronic phase who had failed imatinib therapy.35 Doses of tipifarnib of 300 mg p.o. b.i.d. for the first 14 days of each 21-day cycle were administered with imatinib 300 mg daily. Subsequent doses of 300 and 400 mg, and 400 and 400 mg, respectively, in the same schedule were also administered. Nine patients were treated; three at each dose level. Hematologic responses were seen in patients with abnormal blood counts but none of the patients achieved a cytoge-netic response.35 A second phase I trial also combined tipifarnib with imatinib, but in patients with accelerated (AP) or blastic phase (BP) of CML with hemato-logic relapse or cytogenetic resistance to imatinib. Imatinib was given at 600 mg p.o. daily and combined with escalating doses of tipifarnib (200-600 mg p.o. b.i.d.). The combination therapy was administered for 21 days. Of the six evaluable patients, in the first cohort, three patients reached a complete hema-tologic response. No cytogenetic responses were seen.36

Zolendronate, a bisphosphonate, has been shown to inhibit downstream signaling of Ras in vitro. Additional in vitro and murine model studies have shown synergy between imatinib and zolendronate, providing a rationale for examining this combination in the clinical setting.37

0 0

Post a comment