Viral gene therapy for breast cancer: progress and challenges

ABSTRACT

Introduction: Breast cancer is the most common cancer in women all over the world. Furthermore, up to one third of breast tumors develop metastases that are resistant to standard therapies. Gene therapeutic strategies have been developed in order to specifically target cancer cells either directly or through the stimulation of antitumor immunity.

Areas covered: This review describes the therapeutic strategies that are currently under development to treat this disease using engineered viral vectors including: adenovirus, adeno-associated virus, lentivirus, poxvirus, reovirus, baculovirus, herpesvirus and oncolytic viruses. Advantages and disadvantages of these multiple gene therapy platforms are discussed in detail.

Expert opinion: Metastatic breast cancer is a perfect candidate for gene therapy approaches due to the presence of several tumor antigens and the aberrant expression of many molecular pathways. Oncolytic vectors are able to attack tumor cells while sparing normal cells and their activity is often enhanced by the administration of chemotherapy. However, more efforts are needed in order to reduce toxicity and to achieve better transduction efficiency. Improved preclinical models and a more critical patient selection for clinical trials, along with advances in gene therapy regulations, will surely facilitate the evolution of gene therapy for the treatment of metastatic breast cancer.

KEYWORDS:

• Breast cancer
• metastasis
• viral gene therapy
• oncolytic vectors
• non-replicative vectors

Article highlights

• Metastatic breast cancer is a good candidate for non-replicative and conditionally cytotoxic gene therapy approaches.

• Oncolytic vectors such as herpesvirus, adenovirus, reovirus, poxvirus and Newcastle disease virus are able to replicate within breast tumor cells and spare normal cells.

• Armed oncolytic vectors target additional pathways, such as angiogenesis and antitumor immunity

• Baculoviruses may be good carriers for breast cancer gene therapy.

• Viral gene therapy strategies are appropriate for ex vivo genetic modification of immune cells, such as DC vaccines and adoptive T cell therapy.

• The route of administration could dramatically affect the efficacy of gene therapeutic strategies.

• Neural and Mesenchymal Stem Cells may improve the biodistribution of gene therapy approaches for metastatic breast cancer.

• Viral systems are able to enhance the efficacy of chemotherapy.

• Further studies are needed to develop better gene carriers, improving targeting and transfection efficiency whereas reducing toxicity and avoiding rapid degradation.

• Appropriate tumor models may accelerate translation of experimental gene therapy approaches to the clinical practice.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by the Consejo Nacional de Investigaciones Científicas y Tecnológicas (via grants CONICET PIP 114-201101-00353 to M Candolfi.; PIP 2013-0261 to A Seilicovich as well as doctoral fellowships to MA Moreno Ayala., MF Gottardo., AS Asad) and the Agencia Nacional de Promoción Científica y Tecnológica (via grants PICT-2013-0310 and PICT-2015-3309 to M Candolfi; PICT 2014-0334 to A Seilicovich; PICT 2015-2210 to FA Zanetti and a doctoral fellowship to C Zucatto).