Poster Presentation 27th Lorne Cancer Conference 2015

Therapeutic targeting of polo-like kinase 1 using RNA-interfering nanoparticles (iNOPs) for the treatment of non-small cell lung cancer (#154)

Tanya Dwarte 1 , Joshua McCarroll 1 2 , Huricha Baigude 3 , Jason Dang 3 4 , Lu Yang 1 , Rafael B Erlich 1 2 , Kathleen Kimpton 1 , Joann Teo 1 2 , Sharon Sagnella 1 2 , Mia C Akerfeldt 1 , Jie Liu 5 , Phoebe A Phillips 5 , Tariq M Rana 3 4 , Maria Kavallaris 1 2
  1. Children's Cancer Institute, Randwick, NSW, Australia
  2. ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australian Centre for NanoMedicine, UNSW, NSW, Australia
  3. Program for RNA Biology, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA
  4. Department of Pediatrics, University of California, San Diego, School of Medicine, La Jolla, CA, USA
  5. Pancreatic Cancer Translational Research Group, UNSW, Kensignton, NSW, Australia

Background: Advanced non-small cell lung cancer (NSCLC) remains the most common cause of cancer death worldwide, due to its resistance to chemotherapy, aggressive growth and metastases. Polo-like kinase 1 (PLK1) is a serine-threonine protein kinase which is overexpressed in many cancers, including NSCLC, and plays a major role in regulating tumour growth. The development of PLK1 chemical inhibitors for clinical use has been hindered by poor tumour bioavailability and/or off-target effects. Short-interfering-RNA (siRNA) holds promise as a new class of therapeutics which can selectively silence disease-causing genes. siRNA, however, cannot enter cells without a delivery vehicle.

Aims: To investigate the potential of non-viral, RNAi-interfering nanoparticles (iNOP-7) to deliver siRNA to NSCLC cells and silence PLK1 expression in vitro and in an orthotopic human NSCLC mouse model.

Results: PLK1 was highly expressed in multiple NSCLC cell lines when compared to normal human lung fibroblasts. iNOP-7 was non-toxic, and self-assembled with siRNA and delivered it with high efficiency to NSCLC cells. Furthermore, iNOP-7-PLK1 siRNA potently silenced PLK1 expression by up to 90% in five different NSCLC cell lines. iNOP-7-PLK1 siRNA also markedly reduced NSCLC growth as determined by Alamar Blue assays, and induced apoptosis, as evidenced by an increase in Annexin V, cleaved-caspase 3 and cleaved-PARP expression. Importantly, intravenous delivery of clinically-relevant doses of iNOP-7-PLK1 siRNA reduced lung tumour burden in SCIDbeige mice, measured as a 50% reduction in ex vivo bioluminescence (p=0.006). This result correlated with immunohistochemical staining, which showed reduced Ki67 expression in the tumours of iNOP-7-PLK1 siRNA treated mice.

Conclusion: Collectively, these data indicate that iNOP-7 can complex and deliver siRNA against PLK1 to NSCLC cells, resulting in decreased cell proliferation both in vitro and in vivo. Therefore, iNOP-7-PLK1 siRNA may provide a novel therapeutic strategy for the treatment of NSCLC and other cancers with aberrant PLK1 expression.