Combination of Paclitaxel and MG1 Oncolytic Virus as a Successful Strategy for Breast Cancer Treatment

Marie-Claude Bourgeois-Daigneault; Lauren Elizabeth St-Germain; Dominic Guy Roy; Adrian Pelin; Amelia Sadie Aitken; Rozanne Arulanandam; Theresa Falls; Vanessa Garcia; Jean-Simon Diallo; John Cameron Bell

Disclosures

Breast Cancer Res. 2016;18(83) 

In This Article

Background

Breast cancer is a highly aggressive disease with most of the deaths resulting from metastases within the first three years upon diagnosis.[1] Metastatic human triple-negative breast cancer (TNBC) has the worst prognosis among all types of breast cancer, with high risk of rapid recurrence and shortened survival.[2] TNBC is deficient in the expression of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, and thus, is refractory to conventional breast cancer hormonal therapy such as Tamoxifen. The main therapeutic option with surgery is chemotherapy, but some subsets of tumor are resistant and the prognosis for these patients is poor.[3] The standard of care for TNBC is the administration of anthracyclines and/or taxanes.[2] Paclitaxel (PAC), also called Taxol, is a cancer chemotherapeutic agent of the taxane family that acts by stabilizing microtubules and thus preventing cell division.[4] PAC is commonly used as monotherapy or in combination with different agents. Significant effort is currently being directed toward improving its efficacy and developing alternate strategies for the treatment of chemotherapy-resistant and recurrent disease.

A novel strategy being explored for the treatment of metastatic diseases such as TNBC is the use of oncolytic viruses (OV). Several candidates are currently undergoing clinical trials and are considered promising approaches for the treatment of various cancers including TNBC.[5] At the forefront of this field is T-Vec, a herpes virus that was successfully tested in a phase III study in melanoma and was approved in 2015 by the Food and Drug Administration for clinical use. OVs specifically replicate in and destroy tumor cells by several mechanisms including direct oncolysis.[6] The rhabdovirus family members, vesicular stomatitis virus (VSV) and maraba, were first identified as oncolytic agents by our group.[7,8] The tumor specificity of these viruses is conferred by the capacity of normal cells, but not tumor cells, to respond to antiviral interferons (IFN).[7,8] Variants with a greater therapeutic index, VSVΔ51 and Maraba MG1, were subsequently developed for clinical use.[8,9] Importantly, enrolling recently began for a clinical trial using MG1 both as a stand-alone therapy and in a vaccination strategy in patients with late-stage disseminated disease (NCT02285816).

A means to further improve the efficacy of the virus is to augment its replication in the tumor. In a previous study, we identified drugs, so-called virus sensitizers (VSe), that enhanced VSV replication in a tumor-specific manner.[10] The compound identified as VSe12 in that study is PAC and it demonstrated the ability to substantially increase viral replication in vitro. Another VSe, colchicine, affects microtubule dynamics and was also the subject of a recent detailed study.[11] As opposed to PAC, which stabilizes microtubules, colchicine has a destabilizing effect, which also results in the blockade of cell division.[12] Colchicine-mediated enhancement of VSV was attributed in part to a defect in IFN secretion by infected cells, thus preventing the cytokine-conferred antiviral protection.[11]

The combination of PAC with OV treatment has been tested for vaccinia virus and herpes virus for other indications.[13,14] This study focuses on the efficacy of MG1 for breast cancer treatment and investigates the co-treatment with PAC. Here, using three different murine breast cancer models, we demonstrate that MG1 can be enhanced by PAC both in vitro and in vivo and that the co-treatment improves efficacy better than either treatment on its own without impairing the safety profile of the virus.

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