A/Prof Jake Shortt, Prof Ricky Johnstone
Peter MacCallum Cancer Centre, The University of Melbourne, Monash Heath and Monash University
Lymphoma cells turn on cancer-causing genes that enable them to grow, divide and overrun normal cells. In order for them to be active, these cancer-causing genes are 'read' by bromodomain extraterminal (BET) proteins.
BET inhibitors (BETi) are a new class of designer drug that prevent BET proteins from reading cancer genes. Although this cause may cancer cells to die, a proportion of cells re-express their cancer genes, become resistant to BETi, and relapse.
We have studied and evaluated BETi-resistant lymphomas in mice to establish what causes resistance and how it can be prevented or overcome. This has led to identifying drugs that can kill BETi-resistant lymphomas, either on their own or in combination with BETi. We will now use this data to develop clinical trials for combinations of BETi to maximise their effectiveness for patients.
What is the need?
Aggressive lymphoma is one of the most common and immediately life-threatening blood cancers. About 50% of patients presenting with advanced lymphoma will relapse despite receiving optimal chemo-immunotherapy, which is now the standard treatment. BETi have shown interesting activity (including some remissions) in early clinical trials for patients with aggressive lymphoma. However, only a minority of patients show such notable improvements and we think that most will still relapse. By understanding how a lymphoma resists the BETi we can rationally add other novel drugs to counteract the resistance.
What impact will this research have?
Our research will inform the development of clinical trials for BETi in lymphoma patients, particularly the design of clinical trials where BETi are combined with other novel agents to prevent the emergence of BETi resistance. This will be especially relevant for patients with aggressive lymphoma who require novel treatment options because standard chemo-immunotherapy has failed.
Use genetic manipulation to silence BET proteins in cells instead of BETi to understand how the drug works.
Treat lymphoma-bearing mice with BETi alone and/or the kinase inhibitors where were active in killing lymphoma cells in tissue culture.
|Use DNA sequencing techniques to characterise changes that happen in lymphoma cells when they develop resistance.
"Our research will be especially relevant for patients with aggressive lymphoma who require novel treatment options because standard chemo-immunotherapy has failed."