Evaluating the efficacy and mechanism of action of tyrosine kinase inhibitors in triple negative breast cancer

2021 Honours opportunity

Supervisors: Dr Normand Pouliot and Dr Delphine Denoyer

Laboratory: Matrix Microenvironment and Metastasis

Subjects prerequisites: MED3LAB or MED3PRJ

 

HER2+ve and triple negative breast cancer (TNBC) are aggressive subtypes of breast cancer that have a high propensity to spread (metastasise) to the brain. Antibody-based therapies for breast cancer effectively control systemic disease and extend life in some patients but are largely ineffective against brain metastases due to the poor permeability of antibodies across the blood-brain barrier and/or acquired resistance that almost inevitably develops. Small molecule tyrosine kinase inhibitors (TKIs) provide a promising alternative to antibody due to their high potency, small size and greater brain permeability. We have evaluated the efficacy of multiple TKIs in pre-clinical mouse models of HER2+ve breast cancer brain metastasis and identified neratinib as a potent inhibitor with a unique mechanism of action called ferroptosis, a process distinct from apoptosis. We are currently testing new combination therapies to overcome resistance to neratinib in vitro and in vivo.

This project seeks to extend these findings to TNBC by comparing the efficacy of various TKIs alone or in combination with cell adhesion receptor inhibitors in vitro. Whether neratinib inhibits TNBC growth through ferroptosis or other cell death pathways will be investigated in standard in vitro assays. The efficacy of neratinib mono and combination therapies will be evaluated in mouse models of TNBC metastasis. The project will make use of a variety of techniques including standard cell culture, proliferation assays, metabolic assays, western blotting, flow cytometry, immunohistochemistry, qPCR and animal models.

 

How do I apply?
Please complete and return your Ranked Entry Project Selection Form (available in the 2021 projects bookletby 5pm Friday 6 November 2020 to I.Poon@latrobe.edu.au

How do I find out more?
Discover more about La Trobe University’s School of Molecular Sciences/LIMS Honours opportunities
Contact the LTU Honours Coordinator, Dr Ivan Poon
Phone: 03 9479 6488
E-mail: I.Poon@latrobe.edu.au