Colorectal cancer (CRC) is the 3rd most common cancer worldwide. 85% of CRC arises from mutations in the Wnt signalling pathway. We have shown that AZD1480, a drug that blocks Janus kinases (Jak) can prevent the appearance of Wnt mutant tumours and stop the growth of already established CRC in animal models. This project will test whether Jak inhibitors can improve treatment outcome and prolong disease free survival.
A New Paradigm For Class I Cytokine Receptor Activation
Funder
National Health and Medical Research Council
Funding Amount
$954,946.00
Summary
Class I cytokine receptors include around 30 receptors with diverse functions such as controlling metabolism and inflammation. Cytokine receptors are molecular switches on cells that receive signals from other cells and transmit this signal into the cell’s nucleus to control the regulation of genes. This project will determine the molecular mechanisms involved in class I cytokine receptors and use this knowledge to develop novel ways to modulate these receptors for clinical applications.
Antibody-based Inhibition Of ADAM10 As Cancer Immunotherapy
Funder
National Health and Medical Research Council
Funding Amount
$652,788.00
Summary
Despite our advances in understanding the molecular basis of cancer, treatments for metastatic cancers are limited, emphasising an urgent need for strategies targeting several oncogenic pathways. We generated monoclonal antibodies effectively blocking the activity of ADAM10, an oncogenic cell surface protease that activates tumour growth, invasion and metastasis through multiple pathways. Here we describe the strategies that progress these antibodies as lead therapeutics for clinical testing.
Osteocytic SOCS3 Controls STAT3:STAT1 Balance And Bone Formation
Funder
National Health and Medical Research Council
Funding Amount
$648,164.00
Summary
The most promising new osteoporosis therapy is antibody-based inhibition of the sclerostin protein. We discovered that sclerostin is inhibited by oncostatin M (OSM) only when it binds to a receptor called LIFR, which then activates proteins STAT3 and SOCS3. If OSM binds a different receptor (OSMR) it increases STAT1 activity and destroys bone. This project will determine how to manipulate STAT3, SOCS3, and STAT1 to increase bone formation and provide new treatments for osteoporosis.
ADAM Metalloprotease Inhibition For Treatment Of Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$770,925.00
Summary
Colorectal cancer (CRC) causes over 4000 deaths/year, typically from developing drug resistance and spreading to other organs (metastasis). These processes involve tumour cells called cancer stem cells (CSCs), which rely on specific cell surface proteins for survival and function. We are developing antibodies against one of these type of proteins, to test in mouse models of CRC. These already show promise in targeting CSCs and inhibiting drug-resistance and metastasis in mice.
Controlling Neuroinflammation In Alzheimer's Disease
Funder
National Health and Medical Research Council
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide, with 269,000 Australians currently diagnosed with AD and is expected to soar to about 981,000 by 2050. AD accounts for greater than 60% of all cases of dementia. This grant investigates the role that neuroinflammation plays in the progression and exacerbation of AD and will identify new therapeutic strategies to combat this insidious disease.
Investigating The Roles Of The Wnt And Notch Signalling Systems In Colon Cancer Crypt Biology
Funder
National Health and Medical Research Council
Funding Amount
$604,439.00
Summary
Colon cancer occurs because of mutations to a tumour suppressor gene. These mutations alter the growth and positional signals for the cancer cells. This project aims to produce a computer model of the regulatory processes in normal colonic cells, to discover why the mutations lead to cancer and to discover rational drug targets for interfering with the growth of colon cancer cells.
Mechanism Of Activation Of JAK2 By A Class 1 Cytokine Receptor
Funder
National Health and Medical Research Council
Funding Amount
$562,742.00
Summary
Cytokine receptors regulate key processes such as red/white blood cell formation, stature, adiposity and lactation. They use JAK kinases to signal to regulated genes. Here we will use sophisticated technologies able to observe single molecules and crystallography to uncover the mechanism used by these receptors to signal into the cell using a well characterised, simple cytokine receptor, the growth hormone receptor.
A number of Leukemias, lymphomas and other blood malignancies are caused by mutations in a protein called JAK (Janus Kinase). To combat this human cells produce a protein that inhibits JAK (called SOCS). We aim to study how this process works and to mimic SOCS with a drug in order to treat leukemia.
Colon cancer causes about 4,000 deaths per year in Australia. A better understanding of the biology of colon cancer will lead to new therapeutics that will aim to overcome the treatment resistance. This project is focused on understanding how a novel protein SLIRP regulates colon cancer growth, and will investigate the mechanisms for its protective effects on the disease. If successful, these studies could provide the foundation for targeting SLIRP for therapeutics.