Abstract 2040: Superior therapeutic efficacy of nanoparticle albumin-bound paclitaxel over cremophor-bound paclitaxel in experimental esophageal adenocarcinoma

Abstract

Abstract Introduction: Esophageal adenocarcinoma (EAC) has become the dominant type of esophageal cancer in United States. EAC is the fastest growing cancer in the western world and the overall 5 year survival rate of EAC is below 20 percent. Most patients with EAC present with locally advanced or widespread metastatic disease, where current treatment is largely ineffective. Prognosis for EAC patients remains poor even with combination therapies due to high resistance to chemotherapy. Therefore, new therapeutic approaches are urgently needed. Paclitaxel (PTX) has been used in combination with carboplatin (CP) as a standard combination therapy for advanced EAC. PTX required emulsification with solvents to allow intravenous administration which has resulted in hypersensitivity reactions and potentially dramatic side effects in patients. Nanoparticle albumin-bound (nab) PTX is an albumin-stabilized, cremophor-free and water soluble nanoparticle formulation of PTX. Nab-PTX is a novel microtubule-inhibitory cytotoxic agent and the potential role of nab-PTX has not been tested yet in experimental EAC. Methods: We explored the antiproliferative and antitumor efficacy with survival advantage following CP, PTX and nab-PTX as monotherapy and in combinations in in-vitro, and in murine subcutaneous xenograft and peritoneal metastatic survival models of human EAC. Results: Nab-PTX inhibited in-vitro cell proliferation with significantly lower IC50 (0.25 µM in OE19 and 49 nM in OE33) than that of PTX (0.74 µM in OE19 and 98 nM in OE33) and CP (5.21 µM in OE19 and 1.05 µM in OE33) in OE19 and OE33 EAC cell lines. Nab-PTX treatment resulted in significantly higher antitumour efficacy and survival benefit compared with PTX or CP treatment. After two-week nab-PTX, PTX, CP, nab-PTX+CP or PTX+CP treatments, the average in-vivo local tumor growth inhibition rate was 73, 60, 35, 81 and 68 percent respectively (p=0.025). Nab-PTX treatment increased expression of the mitotic-spindle associated phospho-stathmin, decreased expression of proliferative marker Ki-67 and enhanced apoptosis as confirmed by increased expression of cleaved-PARP and cleaved caspase-3. There was an increase in median animal survival after nab-PTX treatment (65 days) compared to controls (46 days, p=0.0023), PTX (57 days, p=0.0034) or to CP therapy (53 days, p=0.0034). Conclusion: In conclusion, the present study demonstrates that nab-PTX had stronger antiproliferative and antitumor activity in experimental EAC than the current standard chemotherapeutic agents. This strong antitumor activity supports the rationale for clinical evaluation of nab-PTX as promising microtubule-inhibitory agent in EAC. Citation Format: Md Sazzad Hassan, Niranjan Awasthi, Roderich E. Schwarz, Margaret A. Schwarz, Urs von Holzen. Superior therapeutic efficacy of nanoparticle albumin-bound paclitaxel over cremophor-bound paclitaxel in experimental esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2040. doi:10.1158/1538-7445.AM2017-2040