Inhibition of PRMT5 as a cancer therapy

Targeted therapy has had profound impact on outcomes for cancer patients. Nonetheless significant challenges remain to maximize the clinical benefit of targeted therapies including the discovery of targets beyond driver oncogenes, overcoming or preventing resistance, the combination with immunotherapies, and extending their benefit to cancers with poor outcomes.
We have been at the forefront of development of targeted therapies for melanoma through targeting of BRAF, MEK and more recently CDK4. This work has led to a global standard of care for BRAF-mutant melanoma of BRAF + MEK inhibitors and the progress of the combination of BRAF, MEK and CDK4 inhibition into clinical trials. Our recent preliminary studies have identified Protein Arginine Methyltransferase 5 (PRMT5) as a new target for melanoma and potentially oesphageal and pancreatic cancer. In preclinical studies using melanoma cell lines and mouse models we have demonstrated that PRMT5 inhibition synergises with CDK4 and BRAF/MEK inhibitors leading to sustained inhibition of melanoma cell proliferation.
This project will assess the ability of PRMT5 inhibition to be combined with RAF/MEK/CDK4 pathway inhibitors in several cancers and investigate the mechanisms leading to the robust response. In summary this proposal is aimed at improving the clinical benefit of BRAF/MEK and CDK4 inhibitors by combining with PRMT5 inhibition and extending these combination therapies into cancers with poor outcomes (pancreatic and oesophageal). These studies will provide mechanistic insight into the action of PRMT5 inhibitors in RAS/RAF/CDK4 driven tumours and identify patients that will likely benefit from PRMT5 therapy including combination therapy.

The McArthur Molecular Oncology laboratory investigates oncogenes as therapeutic targets for cancer. By targeting oncogenic signalling in cancer and understanding the impact of this therapy on both the tumour cell and its microenvironment, we aim to develop novel treatment strategies that are durable and prevent therapy resistance. The McArthur laboratory has a specific interest in melanoma, but also investigates ovarian, lung, colorectal and haematological cancers.
https://www.petermac.org/research/labs/grant-mcarthur-0


Peter MacCallum Cancer Centre in Melbourne 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.
https://www.petermac.org/education/research-education

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.

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