Abstract 3076: A novel nanoparticle formulation of doxorubicin is clearly differentiated from free doxorubicin in overcoming resistance mechanisms in chemo-resistant tumors
Authors: Trochon-joseph Véronique , Zandanel Christelle , Lemarchand Caroline , Hayes Vincent , Rochas Séverine , Rayah Yamina , Labernardière Jean-Louis , Dixon Graham , Bono Francoise 
Published: July 2017

Background and Aims. Chemo-resistance in hepatocellular carcinoma (HCC) tumor cells can be mediated by several mechanisms including P-gp efflux pumps and drug sequestration by the autophagy process. This study investigates the potential of doxorubicin loaded nanoparticle (NP) to reverse chemo-resistance by these mechanisms compared to free doxorubicin. We present the preclinical evaluation of anti-tumor effects of NP as monotherapy and in combination with standard agents used in treatment of HCC, pancreatic and sarcoma cancers. A phase III clinical study comparing NP to Best Standard of Care (Relive study) in patients with advanced HCC is in the final stages of recruitment with preliminary results expected in 2H 2017.

Methods. Tumor cell lines were incubated with drugs in cell proliferation assay. In vivo efficacy of NP alone (4-8 mg/kg) or in combination with current and investigational treatments for pancreatic cancer (e.g. Gemcitabine, Erlotinib, Abraxane) and HCC (Sorafenib, Regorafenib and Lenvatinib) were performed in mouse tumor models using tumor weight as primary endpoint. In all experiments NP was compared to administration of free doxorubicin. Doxorubicin quantification in tumor and organs to asses PK and biodistribution was also performed using an LC/MS based method. Autophagy was measured by cell proliferation in the presence of inhibitors e.g.. Concanamycin A, Hydroxychloroquine sulfate added 30 min before incubation with the test compound.

Results. NP showed a dose-dependent inhibition of cell proliferation in all resistant cancer cell lines tested with a superior activity compared to free doxorubicin and other tested drugs. In contrast to free doxorubicin, NP showed consistent anti-proliferative activity in the absence/presence of inhibitors of P-gp pumps and autophagy. In a range of in vivo models, NP was preferentially taken up by the tumor tissue and significantly reduced tumor growth when compared with free doxorubicin and with at least equivalent reduction in tumor growth compared to current treatments. Furthermore NP administered in combination with current treatments significantly increased the inhibitory effect of each drug without additional toxicity (as measured by no change in body weight). The results comparing efficacy of NP alone and in combination in HCC, pancreatic and sarcoma cancer models will be presented.

Conclusions. These results demonstrate that NP is clearly differentiated from free doxorubicin, in 1) overcoming resistance mechanisms linked to efflux and autophagy, and 2) having a superior biodistribution profile both of which results in significantly enhanced activity on chemo-resistant tumors. NP also provides an opportunity to combine with other agents, enhancing activity without increasing toxicity. The implications of these results on the further development of NP will be discussed.

Citation Format: Véronique Trochon-joseph, Christelle Zandanel, Caroline Lemarchand, Vincent Hayes, Séverine Rochas, Yamina Rayah, Jean-Louis Labernardière, Graham Dixon, Francoise Bono. A novel nanoparticle formulation of doxorubicin is clearly differentiated from free doxorubicin in overcoming resistance mechanisms in chemo-resistant tumors [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 3076. doi:10.1158/1538-7445.AM2017-3076