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- W2247471250 abstract "4541 Background: Agents targeting microtubules (MTs) are very effective anticancer drugs. Ixabepilone is a novel MT-stabilizing agent active in taxane-refractory models. Prior studies have shown that α-tubulin undergoes post-translational modification following assembly into MTs, including removal of the C-terminal tyrosine, exposing the penultimate glutamic acid (glu-tubulin) and acetylation of lysine 40. Methods: 67 patients with RCC were enrolled on study. 61 patients had a prior nephrectomy and 26 had received at least one prior systemic immune therapy. Treatment consisted of 6 mg/m2 ixabepilone on days 1–5 of a 21 day cycle. Response evaluations were performed every 2 cycles using RECIST. Patients with accessible tumor had biopsies prior to treatment and following the fifth dose of ixabepilone. Protein immunoblots were prepared and probed with antibodies to total and modified α-tubulins, and to β-actin. Results: 402 cycles have been administered. Grade 1, 2, or 3 neurotoxicity was recorded in 15, 17, and 2 patients, respectively. Partial responses have been observed in 8/57 patients with clear cell RCC after 2–9 cycles. MT stabilization was compared in pre- and post-treatment biopsies. Increased glu-tubulin, was observed in 11/12 patients with post-treatment levels 2–25 fold higher than pre-treatment. Similarly 2–100 fold higher acetylated tubulin levels were detected in 10/11 patients. Total α-tubulin levels were increased 2–12 fold (mean = 6.6 ± 3.7) in 8/12 patients, suggesting that tumor cells in some patients adapt to ixabepilone-induced polymerization with new tubulin synthesis. 24 hours after ixabepilone, PBMCs did not show any increase in acetylated or glu-tubulin over basal levels. Because VHL has been shown to stabilize MTs, sequencing is being performed to determine if a correlation exists between response to therapy and VHL status. Conclusions: Ixabepilone is an active agent in RCC, with major clinical responses observed. Assessing levels of glu-tubulin and/or acetylated α-tubulin provides a simple and reliable assay to demonstrate target engagement by MT-stabilizing agents and may help elucidate why these agents succeed or fail. No significant financial relationships to disclose." @default.
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- W2247471250 date "2005-06-01" @default.
- W2247471250 modified "2023-09-26" @default.
- W2247471250 title "A translational study of ixabepilone (BMS-247550) in renal cell cancer (RCC): Assessment of its activity and demonstration of target engagement in tumor cells" @default.
- W2247471250 doi "https://doi.org/10.1200/jco.2005.23.16_suppl.4541" @default.
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