Phase I–II study of vorinostat plus paclitaxel and bevacizumab in metastatic breast cancer: evidence for vorinostat-induced tubulin acetylation and Hsp90 inhibition in vivo

Abstract

Purpose In preclinical models, the histone deacetylase inhibitor vorinostat sensitizes breast cancer cells to tubulin polymerizing agents and to anti-vascular endothelial growth factor (VEGF) directed therapies. We sought to determine the safety and efficacy of vorinostat plus paclitaxel and bevacizumab as first-line therapy in metastatic breast cancer (MBC), and the biological effects of vorinostat in vivo. Patients and Methods Fifty-four patients with measurable disease and no prior chemotherapy for MBC received vorinostat (200 or 300 mg PO BID) on days 1–3, 8–10, and 15–17, plus paclitaxel (90mg/m2) on days 2, 9, 16 and bevacizumab (10mg/kg) on days 2 and 16 every 28 days. The primary objective of the phase I study was to determine the recommended phase II dose (RPTD) of vorinostat, and for the phase II to detect an improvement of response rate from 40% to 60% (alpha =0.10, beta=0.10). Results No dose limiting toxicities were observed, and the RPTD of vorinostat was 300 mg BID. For the primary efficacy analysis in 44 patients at the RPTD, we observed 24 objective responses (55%, 95% confidence intervals [C.I.] 39%, 70%). The adverse event profile was consistent with paclitaxel-bevacizumab, with the exception of increased diarrhea with the addition of vorinostat. Analysis of serial tumor biopsies in 7 patients showed increased acetylation of Hsp 90 and -tubulin following vorinostat. Conclusions Vorinostat induces histone and alpha tubulin acetylation and functional inhibition of Hsp90 in breast cancer in vivo and can be safely combined with paclitaxel and bevacizumab.

A novel HDAC inhibitor OBP-801 and a PI3K inhibitor LY294002 synergistically induce apoptosis via the suppression of survivin and XIAP in renal cell carcinoma

“…Considering the pleiotropic effects of HDAC inhibitors against malignant tumors, their true therapeutic potential most likely lies in combinations with other anticancer drugs (24). Recent clinical trials have indicated that HDAC inhibitors enhance the antitumor activities of several conventional chemotherapeutic and molecular-target drugs (25)(26)(27). Additionally, a previous study showed that HDACs were highly expressed in RCC, suggesting that HDAC inhibitors may be effective on RCC (28).…”

A Phase I/II study of suberoylanilide hydroxamic acid (SAHA) in combination with trastuzumab (Herceptin) in patients with advanced metastatic and/or local chest wall recurrent HER2-amplified breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1104)

“…For the primary efficacy analysis in 44 patients treated at with this SAHA dose, the objective response rate was 55% and SAHA was found to induce tubulin acetylation and Hsp 90 inhibition [28]. …”

Epigenetic therapy of cancer with histone deacetylase inhibitors

“…ORR was 24 out of 54 (55%). [61] Histone deacetylases are crucial components of the oestrogen receptor transcriptional complex. In a preclinical model, HDACI could reverse tamoxifen/aromatase inhibitor resistance in hormone receptor-positive breast cancer.…”