Novel drug combinations targeting chromatin and RNA polymerase I transcription in multiple myleloma

Multiple myeloma (MM) is an incurable cancer with currently available therapies. Single agent therapies rapidly lead to the development of drug resistance and clinical relapse, therefore combination therapies are necessary to provide a more durable response. Growing evidence supports that epigenetic dysregulation, i.e. abnormalities that impair DNA/chromatin function, is an important feature in MM development. Moreover, there are promising novel drugs that target these epigenetic factors entering the clinic for the treatment of MM, presenting an opportunity for investigation of innovative combination therapies.

Our preclinical studies established that selective inhibiton of RNA polymerase I (Pol I) transcription of the ribosomal genes provides a novel therapeutic window in many cancer types. We have intriguing data demonstrating that combining Pol I inhibition with several candidate “epi-drugs” elicits a surprisingly high level of synergy in models of MM. Based on this impressive synergy, this Hons/PhD project aims to conduct epi-drug and genetic screens to not only identify novel drug targets but also uncover key chromatin factors driving the efficacy of these drug class combinations. We will use multiple approaches, including genome-wide, to interrogate the underlying mechanisms of synergy followed by validating promising combinations in mouse models to rapidly progress these findings towards the clinic.

The 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, 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