Congratulations to our four research teams from the School of Medical Sciences who were awarded a total of $3.9m from the 2021 Endeavour Fund round. The Smart Idea Research Projects are:
New chemistry to control kinase cell signalling in disease
Science Leader: Associate Professor Jack Flanagan
A team of investigators from the Auckland Cancer Society Research Centre, Department of Pharmacology, and Department of Molecular Medicine and Pathology lead by Associate Professor Jack Flanagan, Dr Julie Spicer, Professor Peter Shepherd and Professor Bill Denny have won MBIE funding to pursue the development of novel kinase inhibitor chemistry to tackle areas of unmet need in oncology. The research team discovered that Vadimezan, a phase III clinical anti-angiogenic agent developed in the ACSRC during the 1980’s was a broad spectrum, weak kinase inhibitor.
The team built on this result to design new molecules that exhibited a high degree of selectivity with greatly improved potency against several individual kinases relevant to cancer. The major effort to date was on making novel immuno-modulatory agents that block the CSF1R receptor-linked kinase found only in macrophages. The aim was to modulate the immune cell component of the tumour microenvironment to improve therapeutic outcomes. Using 3-dimensional modelling information that showed how the drug binds in the target, the team were able to generate molecules that were very potent against CSF1R activity in macrophage cells. This was the starting point for their current chemistry-driven drug-target discovery approach.
The team current aims include developing novel molecules for subduing T-cell activity by targeting the first kinase in the T-cell receptor signalling pathway. There are applications in some auto-immune diseases and in the control of toxicities associated with different types of T-cell therapies used in cancer treatment. The team is also building on a novel finding that their chemistry showed selectivity for some oncogenic mutations and drug resistant forms of driver kinases found in some gastro-intestinal stromal cancers. They believe this opens up the possibility of targeting the proteins found only in the tumour and not in normal cells. This goal is one of the biggest challenges in cancer-linked kinase drug discovery. The new projects and the earlier lead-up work are possible because the team could draw upon the drug development research including medicinal chemistry, pharmacology and cancer biology accrued over the 60 year history of the Auckland Cancer Society Research Centre.
Sulfate prodrugs for antibody-drug conjugates as anti-cancer agents
Science Leader: Dr Moana Tercel, Auckland Cancer Society Research Centre
Antibody-drug conjugates (ADCs) have recently become established as an effective type of cancer treatment. The goal is to use the selectivity of an antibody to deliver an anticancer drug directly to tumour cells, but in practice, ADCs still cause unwanted side effects for patients. In this project the team of investigators from the Auckland Cancer Society Research Centre lead by Dr Moana Tercel, Dr Frederik Pruijn, Dr. Ben Dickson, and Dr Wouter van Leeuwen will explore a new way to mask the biological activity of drug types that are commonly used in ADCs. Ultimately the team is aiming to make ADCs that are just as effective, but much better tolerated, than current examples.
Novel device for delivering therapies to the inner ear
Science Leader: Professor Peter Thorne, Department of Audiology
This project will develop a novel device to deliver therapies to the inner ear to treat hearing loss. Hearing loss affects about 900,000 people in New Zealand and around 1.5 billion people globally. Team at the University of Auckland is developing drugs and molecular therapies to prevent cellular damage and hence restore hearing or stop hearing loss happening in the first place. A major barrier to effective uptake of these therapies as they come on-stream is the difficulty of getting them into the bone-encased inner ear. They are developing a universal technological approach to deliver therapies directly into the cochlea through the eardrum and overcome the delivery problems. This will allow new therapies to be safely and effectively delivered to the inner ear to relieve hearing loss and recover hearing function.
Improving In Vitro Fertilisation (IVF) success rates through machine learning
Science Leader: Dr Nicholas Knowlton, Department of Molecular Medicine and Pathology
Currently, embryos selected for IVF commonly rely on the basis of features in a single image of the embryo taken at one point in time. While Artificial Intelligence has been used for embryo selection, the team, with access to information on a wide range of aspects of embryo development, will develop a Machine Learning tool to improve the success rates and reduce the waiting times for IVF.