Poster Presentation 27th Lorne Cancer Conference 2015

A COMBINATORIAL APPROACH FOR TARGETED THERAPY OF TRIPLE NEGATIVE BREAST CANCERS: i-PEPS, CHEMOTHERAPY AND NANOPARTICLES (#270)

Anabel Sorolla 1 , Diwei Ho 2 , Callum Ormonde 2 , Edina Wang 1 , K.Swaminathan Iyer 2 , Pilar Blancafort 2
  1. Harry Perkins Institute of Medical Research - University of Western Australia, Nedlands, WA, Australia
  2. The University of Western Australia, Crawley

 Triple negative breast cancers (TNBCs) are responsible for most of the deaths related to breast cancer. They are negative for oestrogen receptor alpha, progesterone receptor and HER2, targets typically explored in the clinic. Current treatment involves chemotherapy but unfortunately, tumour relapses are common. In addition, target selectivity is absent resulting in debilitating systemic side effects. Thus, there is an urgent need to develop novel and more specific therapies to treat this lethal disease. TNBCs show over-expression of the transcription factor Engrailed 1 (EN1) which has been shown to drive resistance to chemotherapy1. The laboratory has recently developed and patented interference peptides (iPeps) which are synthetic peptides designed to bind and inhibit natural transcription factors. We have found that designed iPeps against EN1 (EN1-iPeps) interact synergistically with Docetaxel, a drug commonly used in the clinic for the treatment of breast cancer, at inducing cell death.

Herein we present a nanoparticle delivery system of Docetaxel and EN1-iPeps. Docetaxel was encapsulated within the nanoparticles and EN1-iPeps were bound on the surface of the nanoparticles. The base materials of the nanoparticles are poly(glycidyl methacrylate) polymer decorated with poly(acrylic acid) to create an electrostatically favourable surface that allows for binding of EN1- iPeps2.

We observe that the engineered nanoparticles are efficient at inducing cell death preferentially in the TNBC cell line EN1-enriched T11. They have a lesser effect in the EN1 negative cell line MDA-MB-231 and the normal breast cell line MCF-10A. This supports the specificity of the nanoparticles.

Our in vivo study in mice shows that Docetaxel nanoparticles coated with active EN1-iPeps administered intratumorally significantly hold tumour growth of T11 allografts in comparison with empty nanoparticles coated with mutant or inactive EN1-iPeps.

In conclusion, this innovative construction has the potential to represent the first targeted therapy for TNBCs, which to date, are still incurable. 

  1. Beltran, A. S., L. M. Graves, and P. Blancafort. "Novel role of Engrailed 1 as a prosurvival transcription factor in basal-like breast cancer and engineering of interference peptides block its oncogenic function." Oncogene (2013).
  2. Evans, Cameron W., et al. "Multimodal analysis of PEI-mediated endocytosis of nanoparticles in neural cells." ACS nano 5.11 (2011).