Targeting Breast Cancer and Metastasis by Oligonucleotide Therapeutics with Lipid Nanoparticle (LNP) Delivery System

Suitable for Honours, PhD and clinical students

BACKGROUND

mortality (~90%) is due to metastasis. Breast cancer (BC) is the most commonly diagnosed cancer among women. Of the 10,000 Australians that live with metastatic breast cancer only 32% are alive after five-years (relative survival-rate). While current cancer treatments mostly focus on targeting the primary tumours, the treatment or prevention of metastasis continues to have limited success. We have shown genetic inhibition of Cep55 reduces cancer progression and metastasic potential in mouse models. However, Cep55 is considered undruggable due to its coiled-coil structure; therefore, we have proposed an innovative approach using the antisense-oligonucleotides (ASOs), to inhibit Cep55 expression at the mRNA level. This strategy will generate a proof-of-concept, highlighting the ability and effectiveness of targeting undruggable and hard-to-treat cancers (invasive, aggressive, and advanced cancers) and metastasis preclinically through pilot studies in-vitro and in-vivo.

AIM

1) Screen ASOs in a range of human and mouse metastatic and triple-negative breast cancer cell lines.

2) Evaluate preclinically whether ASO-Lipid nanoparticles (LNP) impedes breast cancer growth, progression, and spread and examining the efficacy, stability, specificity, and toxicity in-vivo.

3)  Investigate the mechanism of action and functional role of Cep55 in tumor-microenvironment and metastasis by spatial transcriptomics.

SIGNIFICANCE

To overcome the challenge of undruggable cancer targets, we will use ASOs which target mRNAs and this strategy can be expanded to other undruggable targets in cancer. We utilised the next-generation ASOs design which enhances the potency, stability, binding properties, reduced toxicity, pro-inflammatory and off-target effects, improved therapeutic index, and extended duration of effect. In our human cells and mouse models, we will test the efficacy of LNP-based drug delivery which shall protect ASOs from degradation and permit cellular uptake and drug release. We expect this project will generate proof-of-concept data on the effectiveness of the ASO-LNP system and provide an on-target mechanistic validation in preclinical models of breast cancer.  We anticipate this strategy pave the way for a resolution to treat patients with aggressive cancers and overcome the metastatic burden. 

TASKS

This project will apply a wide range of techniques in medical research, cell biology and tumour immunology to target the cancer cells, mouse works and the student will become familiar with these techniques and possibly be involved in the publication depending on the achieved results.