Abstract
8014 Background: Ras-based signaling is thought to be critical in the genesis of melanoma. Farneslytransferase (FT) inhibitors (FTIs) have been developed as a pharmacologic strategy to inhibit Ras function. Additional farnesylated proteins are also important for the malignant process, and FTIs inhibit melanoma cell line proliferation in vitro. These considerations motivated the development of a phase II trial of the FTI R115777 in patients with melanoma. Farnesylated proteins are also important for T cell activation. The interest in future combinations of targeted agents and immunotherapeutics in this disease prompted analysis of T cell function ex vivo. Methods: A 3-stage design was pursued with a maximum of 40 patients planned and early stopping if there were no responders in the first 14, or fewer than 2 responders in the first 28 patients. Eligibility included intact organ function, PS≤1, no prior chemotherapy, at most 1 prior immunotherapy, no brain metastases, and presence of at least 2 cutaneous lesions amenable to excisional biopsy. R115777 (300 mg orally) was administered twice per day for 21 days of a 28-day cycle. Patients were evaluated every 2 cycles by RECIST criteria. Blood was obtained pre-treatment and during week 7 for analysis of HDJ-2 farnesylation and for T cell IFN-γ production in response to SEA. In addition, tumor biopsies were performed pre- and post-treatment when feasible to directly measure FT activity. Results: 14 patients were enrolled. 2 patients had grade 3 toxicities, which included myelosuppression, nausea/vomiting, elevated BUN, and anorexia. There were no clinical responses, and only 4 patients went on to a second course of treatment. All analyzed patients showed HDJ-2 gel shift in peripheral blood cells, as well as marked inhibition of FT activity (by 85–98%) in tumor tissue. T cell production of IFN-γ was also suppressed. Conclusions: Despite potent target inhibition, the FTI R115777 showed no evidence for clinical activity as a single agent in this cohort of 14 metastatic melanoma patients. Inhibition of T cell function has implications for future combination therapies and suggests the possibility for FTIs as candidate immunosuppressive agents. New therapeutic approaches for melanoma, or logically selected combination therapies, are needed. [Table: see text]
Highlights
Multiple farnesylated proteins are involved in signal transduction in cancer
Patient characteristics Fourteen patients with metastatic melanoma were enrolled in this study between May 2003 and April 2005
We recently reported that Farnesyltransferase inhibitors (FTIs) can inhibit T cell activation through the T cell receptor (TCR) complex [41]
Summary
Multiple 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 farnesylated proteins are important for T cell activation, measurement of effects on T cell function was pursued. Metastatic melanoma is difficult to treat and it is only recently that therapy has been shown to have an impact on overall survival [1,2,3]. The vast majority of melanomas have activating mutations in signaling proteins involved in the RAS pathway. Mutated BRAF can be effectively targeted in patients with metastatic melanoma, with impressive response rates in early phase trials [14,15,16]. Recent data demonstrates an improvement in overall survival in patients treated with selective BRAF inhibitors when compared to dacarbazine, many patients relapse, further highlighting the importance of understanding the molecular pathogenesis of this disease [2,17]. Transgenic mouse experiments have confirmed the important contribution of activated RAS-based signaling to melanomagenesis in vivo [22,23,24]
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