Testing a promising targeted therapeutic for triple-negative breast cancer

Overview

Triple-negative breast cancers (TNBC) are negative for Estrogen Receptor, Progesterone Receptor and HER2 expression, are clinically aggressive and cannot be treated with the available hormonal or targeted drugs used for other breast cancer subtypes. TNBC accounts for 15-20% of all invasive breast cancer and patients have increased risk of recurrence, mortality and metastases early during disease progression. There is an urgent clinical need to develop improved treatment strategies for these women since the median survival of patients with metastatic TNBC is around 13 months, and virtually all women with metastatic TNBC succumb to their disease despite systemic therapy. Growth factor receptors are commonly hyperactivated in human TNBC, but the underlying mechanisms remain elusive. Neuropilin-1 (NRP1) is a cell surface co-receptor that activates a spectrum of receptor tyrosine kinase pathways that drive cancer progression. We have discovered that NRP1 protein is dramatically over-expressed in a subtype of TNBC called Claudin-low. Claudin-low tumours are the most aggressive and metastatic and least differentiated amongst TNBC. NRP1 is required for the growth and proliferation of Claudin-low cell lines and in vivo tumour growth. Our preliminary data indicates that therapeutic inhibition of NRP1 blocks the growth of Claudin-low xenografts in mice. We hypothesise that NRP1 regulates the activation of multiple pro-tumourigenic pathways in Claudin-low tumours and is essential for their growth and survival. This project aims to exploit this key feature as a potential therapeutic vulnerability in Claudin-low TNBC.

Approaches/skills and techniques

1. Identify NRP1-activated signalling pathways mediating the growth and survival of Claudin-low tumours. NRP1-interacting receptors and downstream signalling nodes in Claudin-low cell lines will be identified by phospho-antibody arrays and validated by western blotting. Transcriptional changes in response to NRP1 inhibition will be characterised by RNA-sequencing to reveal NRP1-regulated signalling networks.
2. Determine whether NRP1 expression in human TNBC can predict clinical outcomes. Immunohistochemistry for NRP1 will be performed on patient TNBC tissue specimens obtained from several clinical cohorts with long-term follow up at different stages of disease progression. Pathologist scoring will allow correlation of NRP1 expression with patient outcome and therapy responses.
3. Pre-clinically test an NRP1 inhibitor on Claudin-low tumours in mice. A clinically developed NRP1 inhibitor will be tested for ability to control growth of Claudin-low xenograft models representing a clinically relevant spectrum of metastatic and non-metastatic Claudin-low variants. Tumours will be assessed for expression of key NRP1 downstream mediators identified in Aim 1 by immunohistochemistry to determine the effects of NRP1 inhibition on pathway activity.

Outcomes

This work will establish the functional and biological effects of NRP1 in Claudin-low TNBC, the predictive utility of NRP1 and associated proteins in TNBC patient outcomes, the role of NRP1 in promoting aggressive tumour progression and the efficacy of NRP1 inhibition in preclinical models.

Keywords

• breast cancer
• cancer
• metastasis
• therapy

Contact

Contact the supervisor for more information.