Donald R. Hawken

Synergistic Antitumor Activity of Ixabepilone (BMS-247550) Plus Bevacizumab in Multiple In vivo Tumor Models

Purpose: Angiogenesis is a critical step in the establishment, growth, and metastasis of solid tumors, and combination of antiangiogenic agents with chemotherapy is an attractive therapeutic option. We investigated the potential of ixabepilone, the first in a new class of antineoplastic agents known as epothilones, to synergize with antiangiogenic agents to inhibit tumor growth. Experimental Design:In vitro and in vivo cytotoxicity of ixabepilone as single agent and in combination with two targeted antiangiogenic agents, bevacizumab or sunitinib, were examined in preclinical tumor models. Direct effects of the agents against endothelial cells was also examined and compared with the effects of paclitaxel as single agent and in combination with bevacizumab. Results: Ixabepilone showed robust synergistic antitumor activity in combination with bevacizumab and sunitinib in preclinical in vivo models derived from breast, colon, lung, and kidney cancers. The synergistic antitumor effect was greater with ixabepilone compared with paclitaxel. Furthermore, ixabepilone was more effective than paclitaxel at killing endothelial cells expressing P-glycoprotein in vitro and inhibiting endothelial cell proliferation and tumor angiogenesis in vivo. Conclusions: Ixabepilone may enhance the antitumor effects of antiangiogenic therapy by direct cytotoxicity and also indirectly via the killing of tumor-associated endothelial cells. Given that ixabepilone has reduced susceptibility to drug efflux pumps compared with taxanes, these data may explain the increased antiangiogenic and antitumor activity of ixabepilone in combination with antiangiogenic agents. Phase II studies to assess the efficacy and safety of ixabepilone plus bevacizumab in locally recurrent or metastatic breast cancer are planned.

Abstract C18: Assessment of Gli1 expression during skin regeneration in mouse models and normal healthy volunteers

Background: Inhibition of the Hedgehog pathway using Smoothened antagonists is emerging as a promising targeted therapy for cancers with pathway activating mutations or dysregulated expression. In support of the clinical development of BMS‐833923 (XL139), an orally available, potent Smoothened antagonist, a pharmacodynamic assay was developed to measure Gli1 protein expression during the wound healing process. Results: Gli1 protein and mRNA expression were first examined by immunohistochemistry or RT‐PCR in mouse skin at baseline and in regenerating skin at various time points following the initial punch biopsy. The effects of BMS‐833923 treatment on pathway expression profiles were then determined. The results showed that in control mice, Gli1 protein levels were elevated at as early as 3h and sustained for up to 72h. The intensities of Gli1 staining in both hair follicles and epidermis were greatly enhanced. However, in the mice treated with BMS‐833923 at the time of initial biopsy, the magnitude and duration of Gli1 up‐regulation were greatly reduced. While the Gli1 protein level was elevated within 6h, it returned to nearbaseline levels at 24h and remained low thereafter. Gli1 mRNA expression data support these observations. To better define the timing of potential Hedgehog pathway activation in human skin, an experimental medicine study was conducted to examine the expression of Gli1 after skin wounding and during regeneration in eighteen normal healthy volunteers. The baseline skin was sampled at the nape of the neck and the regenerating skin sample completely encompassed the initial wound. The intensities of both nuclear and cytoplasmic staining, as well as the percent cell staining positivity were scored. The data indicated that Gli1 protein was significantly up‐regulated at 6h and 24h following wounding. Conclusion: Gli1 protein level at 24h post‐skin wounding assessed by immunohistochemistry is currently being used as a surrogate tissue pharmacodynamic measurement in a first‐in‐human multiple ascending dose trial in subjects with advanced or metastatic solid tumors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C18.