Acute Myeloid Leukaemia (AML) is an aggressive disease with poor prognosis and development of novel treatment options is urgently needed. Isocitrate Dehydrogenase (IDH)-1 and -2 catalyse the conversion of isocitrate to a-ketoglutarate (a-KG), a crucial metabolite that is an intermediate in the TCA cycle and an essential co-substrate for >60 enzymes with a wide range of functions. IDH1 and -2 mutations occur in ~20% of AML as well as a range of other cancers and pre-malignancy syndromes. Mutations typically confer on the enzymes a novel ability to produce D-2-hydroxyglutarate (2-HG), a molecule that is structurally similar to a-KG and can act as an inhibitor or activator of a-KG-dependent enzymes.
We and others have recently shown that IDH mutations can contribute to leukaemia initiation and maintenance both in vitro and in vivo; and small molecule inhibitors that block production of 2-HG have recently entered clinical trials. However, the precise mechanism and genetic determinants of therapy response to IDH inhibition remain unknown.
The specific aims of this study are to:
(1) Develop a series of clinically relevant, genetically engineered murine AML models wherein expression of mutant IDH is inducible;
(2) Evaluate the requirement for continued expression of mutant IDH for prolonged leukaemia growth and survival by genetically depleting expression (genetic de-induction) and pharmacologically inhibiting the mutant enzymes; and
(3) Understand the mechanism of disease regression following genetic de-induction and pharmacological inhibition of mutant IDH.
In the Kats laboratory we are interested in developing new therapeutic strategies for aggressive blood cancers. We use advanced genetic tools and small molecule inhibitors to uncover oncogene dependencies and synthetic-lethal interactions in genetic contexts that occur commonly in human cancer. https://www.petermac.org/research/labs/lev-kats
Peter MacCallum Cancer Centre, Melbourne Australia
Peter MacCallum Cancer Centre is Australia’s only public hospital solely dedicated to cancer, and home to the largest cancer research group in Australia. Cancer is a complex set of diseases, and modern cancer research institutes such as Peter Mac conduct research covering a diversity of topics that range from laboratory-based studies into the fundamental mechanisms of cell growth, translational studies that seek more accurate cancer diagnosis, clinical trials with novel treatments, and research aimed to improve supportive care.
All students engaged in postgraduate studies at Peter Mac are enrolled in the Comprehensive Cancer PhD (CCPhD) program, regardless of which university they are enrolled through. The program is managed by the Sir Peter MacCallum Department of Oncology (The University of Melbourne), based at Peter Mac.
Tapping into the depth and breadth of knowledge and experience offered by the ten partners of the Victorian Comprehensive Cancer Centre (VCCC) alliance, the University of Melbourne’s Comprehensive Cancer PhD Program provides a unique opportunity for multidisciplinary cancer-related PhD candidates to experience clinical and research activities across the alliance.
The Comprehensive Cancer PhD program builds on established conventional training for cancer research students providing a coordinated program of skills, research and career training in addition to usual PhD activities. The program is designed to complement existing PhD activities and provides opportunities to develop professional skills that will help candidates to fulfil their career ambitions. https://www.petermac.org/education/comprehensive-cancer-phd-program