Dr Stephanie Grabow
Researcher: Dr Stephanie Grabow
Institute: Walter and Eliza Hall
Institute of Medical
Project title: Harnessing the cell death pathway to
develop novel therapies for leukaemia
Disease focus: Leukaemia and lymphoma
Annual Funding: $100,000
Funding period: 2015-2016
Researchers at the Walter and Eliza Hall Institute of Medical Research (WEHI) are investigating new avenues to develop a new anti-cancer treatment for lymphoma and leukaemia. One of these avenues is to target MCL-1, a protein that is critical for the survival of many cell types.
Up to 70% of human cancers, particularly leukaemias and lymphomas, show deregulated MYC protein. This allows cells to divide abnormally and, together with other genetic defects, can cause tumour development. In previous work, Dr Stephanie Grabow and her colleagues at WEHI discovered that leukaemia and lymphoma cells that arose due to deregulated MYC are exquisitely dependent on MCL-1 for their survival. In fact, many tumour cells are more dependent on MCL-1 than normal healthy cells, suggesting that drug targeting of MCL-1 may be feasible for cancer therapy.
To determine the therapeutic potential of MCL-1 inhibitory drugs and their possible adverse effects on patients, Dr Grabow will gather vital information about the amount of MCL-1 protein required during lymphoma development and continued growth of tumour cells and compare this to the extent of MCL-1 reduction that normal tissues can tolerate to avoid unacceptable damage.
“The data I gather will help us understand what concentration of MCL-1 inhibitory drug is needed to effectively kill leukaemia and lymphoma cells without causing adverse side-effects,” she said.
“We have highly promising preliminary results testing a potential drug in laboratory models of various human lymphomas and leukaemias,” said Dr Grabow.
“I am also looking at the role of key ‘pro-death’ proteins to understand how they interact with MCL-1 to control the survival of cancer cells and the normal tissue cells.
“It’s possible that cancer cells may be able to adjust to a reduction in MCL-1 levels by decreasing the production of pro-death proteins (or increasing related pro-survival proteins). Hence, a combination of these proteins may have to be targeted by drugs to achieve the most efficient therapeutic effect."
Another component of Dr Grabow’s research is to identify gene mutations commonly found in leukaemias and lymphomas that correlate with high dependency on MCL-1 for survival. This work is geared to identify diagnostic biomarkers for lymphomas and leukaemias that will benefit the most from drugs that inhibit MCL-1.
Knowledge gained from Dr Grabow’s studies will contribute to the development of novel drugs that specifically target MCL-1 or regulators that control its level and activity for anti-cancer therapy.
WEHI Molecular Genetics of Cancer Division and Laboratory Head, Professor Andreas Strasser is supervising Dr Grabow’s research.
The Leukaemia Foundation also awarded a PhD scholarship to Margs Brennan (working in the same research division as Dr Grabow), who is investigating the mechanisms that control the expression of MCL-1 and the potential of drugs that inhibit MCL-1 for the treatment of leukaemias and lymphomas. The Leukaemia Foundation already partly-funded this laboratory’s ground-breaking research into MCL-1 published by Dr Gemma Kelly.