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mRNA translation reprogramming and metabolic re-wiring in response to ribosome-targeted therapies


Project Description

Increased synthesis and activity of ribosomes are associated with oncogenesis downstream of the major oncogenes including MYC, RAS and PI3K. We developed the selective inhibitor of ribosome biogenesis, CX-5461, which targets RNA Polymerase I transcription, suppressing ribosomal RNA synthesis. We have showed that combining CX-5461 with inhibitors of mRNA translation markedly improved the efficacy of treating MYC-driven lymphoma and prostate cancer. We further demonstrated that targeting of ribosome biogenesis and function results in rapid and specific inhibition of translation of mRNAs encoding translation factors and metabolic regulators and that resistance to this therapy is associated with enhanced translation efficiency of these mRNAs. We hypothesize that (i) targeting oncogene-driven translational re-wiring of key cellular processes will be a common mode of action of ribosome targeted therapies and (ii) definition of the key networks associated with resistance will enable the rational design of effective combination therapies for oncogene driven cancers.

The project specific aims are to:
1. Identify and characterise additional drivers of resistance of MYC-driven lymphoma to ribosome-targeting therapies by a comprehensive program of polysome profiling, genome sequencing and high-throughput genomic screens.
2. Investigate the effectiveness of targeting mRNA translation or metabolic pathways in multiple mouse models of MYC-dependent blood cancer.


Researchers in the Pearson laboratory investigate the molecular basis of the regulation of signalling pathways and their control of cell growth, to understand how deregulation of this process contributes to cancer and how it can be targeted to treat the disease. We aim to understand how deregulation of this process contributes to cancer and how it can be targeted to treat the disease, by:
1) Understanding the signal transduction pathways underpinning cell growth control.
2) Conducting biochemical and cell biology analysis of the role of deregulated cell growth in cancer.
3) Analysing novel therapies targeting cell growth to treat cancer in pre-clinical models of lymphoma, ovarian and prostate cancers.
4) Pharmacogenomic analysis of the pathogenesis of ovarian cancer and predictors of response to emerging targeted therapies.
https://www.petermac.org/research/labs/rick-pearson

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

Funding Notes

All PhD students at Peter Mac must have a scholarship from The University of Melbourne or through another government, trust or philanthropic organisation. Before applying for a scholarship, you must have agreed on a project with an institute supervisor.

For further information about the university application process, see:
View Website

For further information regarding scholarships (both local and international), see:
View Website
Closing dates for applications for scholarships to commence in 2020: Round 1 -31 October 2019; Round 2 - 31 Jan 2020; Round 3 - 15 May 2020.

References

1. Cancer Genome Atlas Research N. Integrated genomic analyses of ovarian carcinoma. Nature. 2011; 474(7353):609-615.
2. Bywater MJ, et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell. 2012; 22(1):51-65.
3. Devlin JR, et al. Combination therapy targeting ribosome biogenesis and mRNA translation synergistically extends survival in MYC-driven lymphoma. Cancer Discov. 2016.
4. Hein et al., Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population. Blood (2017) [Epub ahead of print]
5. Quin J, et al. Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling. Oncotarget. 2016.

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