Cynthia Bucher

Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104)

BackgroundMultiple farnesylated proteins are involved in signal transduction in cancer. Farnesyltransferase inhibitors (FTIs) have been developed as a strategy to inhibit the function of these proteins. As FTIs inhibit proliferation of melanoma cell lines, we undertook a study to assess the impact of a FTI in advanced melanoma. As farnesylated proteins are also important for T cell activation, measurement of effects on T cell function was also pursued.MethodsA 3-stage trial design was developed with a maximum of 40 patients and early stopping if there were no responders in the first 14, or fewer than 2 responders in the first 28 patients. Eligibility included performance status of 0–1, no prior chemotherapy, at most 1 prior immunotherapy, no brain metastases, and presence of at least 2 cutaneous lesions amenable to biopsy. R115777 was administered twice per day for 21 days of a 28-day cycle. Patients were evaluated every 2 cycles by RECIST. Blood and tumor were analyzed pre-treatment and during week 7.ResultsFourteen patients were enrolled. Two patients had grade 3 toxicities, which included myelosuppression, nausea/vomiting, elevated BUN, and anorexia. There were no clinical responses. All patients analyzed showed potent inhibition of FT activity (85-98%) in tumor tissue; inhibition of phosphorylated ERK and Akt was also observed. T cells showed evidence of FT inhibition and diminished IFN-γ production.ConclusionsDespite potent target inhibition, R115777 showed no evidence of clinical activity in this cohort of melanoma patients. Inhibition of T cell function by FTIs has potential clinical implications.Clinicaltrials.gov number NCT00060125

The Pursuit of Potent Anti-influenza Activity from the Antarctic Red Marine Alga Gigartina skottsbergii

With an estimated 3–5 million infections and as many as 500,000 deaths from the complications of influenza infections each year, there is a critical need to identify novel drug classes and structures that can be exploited for antiviral development. A bioassay-guided fractionation of extracts from the red marine algae Gigartina skottsbergii, collected near Anvers Island, Antarctica, has yielded fractions that significantly inhibited the replication of influenza viruses A/Wyoming/3/2003 (H3N2) and A/WSN/1933 in vitro with an IC50 value of 4–8 μg/mL. The antiviral effect was dose dependent, strain specific, and selective as the virus-induced cytopathogenic effect (CPE) was reduced at nontoxic concentrations of the extract. SDS-gel electrophoresis and sequencing of the active fraction suggested homology with lectins. Insight into the mechanism of action via hemagglutination and plaque assay indicates that the antiviral effect occurs early during viral infection by interfering with virus-receptor interactions. This study suggests that activity from current over-the-counter anti-influenza vitamin supplements prepared from the same algal species may not completely arise from the previously reported antiviral sulfated polysaccharides.