Abstract 4717: Effective preclinical management of angiosarcoma with oral paclitaxel

Abstract

Abstract Angiosarcomas are characterized by proliferating anaplastic cells derived from blood vessels. While there is a lack of approved treatments for angiosarcomas, weekly intravenous (IV) paclitaxel has shown some benefit. However, IV paclitaxel therapy is commonly accompanied with hypersensitivity reactions and irreversible neuropathy. Oral paclitaxel (“Oraxol”; paclitaxel co-administered with HM30181A, a non-absorbable P-gp inhibitor) eliminates the risk of hypersensitivity to IV formulations while reducing neuropathy with the potential for improved efficacy. Oral paclitaxel is currently being tested in a pivotal phase III trial for metastatic breast cancer in addition to multiple phase I/II trials for solid tumors. Here, we aim to expand the therapeutic application of oral paclitaxel to the treatment of angiosarcomas. An MTT assay was utilized to determine the potency of paclitaxel against mouse angiosarcoma cell lines (MS1, SVRA221a, and SVRbag4) and a human endothelium cell line (HMEC-1). The potency (IC50) of paclitaxel was estimated to be 1.8 ± 0.36 ng/mL for MS1, 1.8 ± 1.0 ng/mL for SVRA221a, 3.9 ± 1.0 ng/mL for SVRbag4, and 0.46 ± 0.23 ng/mL for HMEC-1 cells. Immunofluorescence was used to examine the effect of paclitaxel on microtubule polymerization in the angiosarcoma cell lines. Paclitaxel induced polymerization of microtubules accompanied with condensed and rounded morphology starting at 4.2 - 8.5 ng/mL. To assess the efficacy of oral paclitaxel, MS1, SVRA221a, and SVRbag4 xenograft models were developed. The MS1 tumors grew too slowly while the SVRbag4 tumors did not reach tumor size endpoint due to necrosis and ulceration, so tumor doubling time and tumor growth delay could not be determined. In the SVRA221a angiosarcoma xenograft model, oral paclitaxel administered for three consecutive days, weekly for three weeks, resulted in dose-dependent tumor growth inhibition and subsequent increased survival. Mice treated with 20 mg/kg HM30181A and 30 mg/kg paclitaxel experienced the greatest tumor growth inhibition with 57.5% survival on Day 15, whereas 20 mg/kg and 40 mg/kg paclitaxel administered with 20 mg/kg HM30181A demonstrated 32.3% and 51.6% survival on Day 15 of treatment, respectively. The antitumor effect and increased survival appeared to plateau between 30 and 40 mg/kg, suggesting that increasing the dose above 30 mg/kg provides no additional benefit. Cavernous blood-filled neoplastic vessels were consistently formed in vehicle and 10 mg/kg paclitaxel-treated groups. However, few to none were present in 20, 30, or 40 mg/kg paclitaxel-treated groups, suggesting oral paclitaxel demonstrated dose-dependent efficacy in this angiosarcoma murine model. Oral paclitaxel has been granted Orphan Drug Designation by the US FDA for the treatment of angiosarcomas and a pilot study of oral paclitaxel in patients with cutaneous angiosarcoma is planned (NCT03544567). Citation Format: Murray J. Cutler, Krista E. Belko, Yahao Bu, Alissa R. Verone-Boyle, David Cutler, Wing-Kai Chan, Rudolf Kwan, Johnson Y. Lau, Michael P. Smolinski. Effective preclinical management of angiosarcoma with oral paclitaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4717.