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Activation of nucleolar-specific DNA damage response as a therapeutic strategy for ovarian cancer

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  • Full or part time
    Dr E. Sanij
    Prof R. Pearson
  • Application Deadline
    Applications accepted all year round

Project Description

Ovarian cancer is the major cause of death from gynecological cancers. The most common and aggressive subtype, high-grade serous ovarian cancer (HGSOC), accounts for 70-80% of all ovarian cancer deaths [1]. HGSOC patients are treated by surgery and/or chemotherapy, yet within 5 years most of these women relapse making new treatment options essential.

We developed a “first in class” drug, CX-5461 that inhibits RNA polymerase I transcription, selectively kills cancer cells [2-4] and is in clinical trials in haematologic (Peter Mac) and breast cancers (Canada). Importantly, our studies demonstrate substantial efficacy of CX-5461 in HGSOC, which is the basis of a new trial in HGSOC we are planning in 2018. 50% of HGSOC is characterized by frequent alterations of genes involved in the homologous recombination (HR) DNA repair pathway. Aberrations in DNA repair provide a weakness that can be exploited therapeutically with genotoxic chemotherapy and inhibitors of DNA repair such as PARP inhibitors (PARPi), now approved in the clinic.

Our data demonstrate that CX-5461 in combination with PARPi has significant therapeutic benefit in vivo against HGSOC xenograft models. Thus, we aim to provide direct evidence for the effectiveness of these strategies to facilitate clinical trials that will eventually lead to improved outcomes for HGSOC patients. This project aims to investigate the molecular mechanisms underlying the improved efficacy of CX-5461 in combination with DNA repair and DNA damage response inhibitors against ovarian cancer. Specifically, we aim to characterise the molecular and cellular response to CX-5461 in combination with PARPi and cisplatin (chemotherapy) in primary and cancer ovarian cell lines.

The Pearson laboratory investigates the molecular basis of the regulation of signalling pathways and their control of cell growth. 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.

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.

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 regarding scholarships (both local and international), see Melbourne Scholarships
Closing date for applications for scholarships to commence in 2015: 31 October 2014.

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