Laboratory for cancer medicine


Student project opportunities

Investigating the therapeutic potential of ciclopirox olamine for treatment of metastatic melanoma

Research area: Potential new treatment for metastatic melanoma
Laboratory: Laboratory for Cancer Medicine
Project suitable for: Honours
Essential qualifications: BSc with a background in some molecular biology
Chief supervisor: Professor Peter Leedman
Other supervisors: Rikki Brown
Start date: January 2017, or earlier if suitable

Project outline 

The outlook for patients with advanced melanoma has been transformed in recent years with the development of targeted and immune therapies. Approximately 50% of patients have a mutation in the gene BRAF, which leads to aberrant signaling of the MAPK pathway to promote melanoma growth and metastasis. Accordingly, targeted inhibitors have been developed to target these pathways and have shown great promise in the clinic. However, a significant therapeutic challenge in melanoma remains the development of resistance to these targeted inhibitors, which occurs in virtually all patients. Hence, further investigation of the molecular mechanisms of drug resistance and the development of new therapeutic approaches is urgently required. 

Ciclopirox olamine (CPX) is a topical anti-fungal agent that is being repositioned for the treatment of hematological malignancy. Preliminary studies in our laboratory indicate potential therapeutic efficacy of CPX for metastatic melanoma. This project aims to investigate the potential of CPX for the treatment of metastatic melanoma in BRAF wild type and BRAF mutant cells that may be sensitive or resistant to MAPK inhibitors.
This project will assess the effects of CPX on melanoma growth, survival and cell cycle. Gene expression profiling will be used to delineate the mechanism by which CPX acts on melanoma cells. One or more of the key genes identified will be further characterised in melanoma cells as potential drivers of the CPX effect. Additionally the project will utilize xenografts as a model of melanoma to assess whether CPX can inhibit tumour growth in vivo.
This project provides an opportunity to work with enthusiastic scientists in a laboratory with a strong track record, use exciting techniques and identify novel pathways regulated by a drug that can potentially be rapidly translated to the clinic to treat metastatic melanoma.

Contact
Professor Peter Leedman  - peter.leedman@perkins.uwa.edu.au

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Characterising the role of mirR-7 in therapeutic sensitivity in liver cancer

Research area: microRNAs and cancer
Project suitable for:PhD
Essential Qualifications: BSc with a background in molecular biology
Chief supervisor: Professor Peter Leedman
Other supervisors: Dr Tasnuva Kabir 
Start date: January 2017, or earlier if suitable

Project outline 

Liver cancer is emerging as a major global health problem, with the incidence rising rapidly and there being little effective therapy and patients having an extremely poor outlook. In liver cancer, a targeted drug called sorafenib is the current standard of care for patients with advanced disease. Although initially successful in suppressing tumour growth in many patients, resistance to the drug is common, leading to recurrence of the disease and widespread metastasis. Hence, identifying ways to overcome sorafenib resistance is a high priority in the field. 

microRNAs (miRs), short non-coding RNAs, are playing an increasingly important role in human cancer. Our Laboratory has generated extensive data on miR-7, which is a potent tumor suppressor in several cancers. We have recently shown miR-7 to be a potent inhibitor of liver cancer cell growth both in vitro and in vivo.

This project aims to investigate the effects of miR-7 in combination with sorafenib and other agents, such as erlotinib (an EGFR inhibitor) and miR-34a (a tumour suppressor miR), on liver cancer cell growth and therapeutic resistance. Initially, this will involve several in vitro assays to determine whether miR-7 works in combination with these agents to inhibit key processes and signalling pathways. Following this, the best combinations will be investigated further in multiple complementary in vivo approaches to assess the effect on tumour growth. An additional aspect of the project will be to investigate whether miR-7 can restore sensitivity in sorafenib-resistant liver cancer cells which we have generated in the laboratory. 
This project provides an opportunity to work in the area of microRNAs and cancer in a laboratory with a strong track record in the functional biology of these molecules, utilise a broad range of exciting in vitro and in vivo techniques, and characterise a novel approach to overcoming therapeutic resistance (arguably one of the highest priority areas in cancer biology today).


Contact
Professor Peter Leedman  - peter.leedman@perkins.uwa.edu.au



Synthetic lethal screeens to identify microRNAs that rescue therapeutic sensitivity in liver cancer 

Research area: MicroRNAs and cancer
Laboratory: Laboratory for Cancer Medicine
Project suitable for: Honours
Essential qualifications: BSc with a background in some molecular biology
Chief supervisor: Professor Peter Leedman
Other supervisors: Dr Tasnuva Kabir 
Start date: January 2017, or earlier if suitable

Project outline

microRNAs (miRs), short non-coding RNAs, are playing an increasingly important role in human cancer. Our Laboratory has generated extensive data on several miRs and cancer, especially miR-7. miR-7 plays a key role to suppress cancer cell signalling via the epidermal growth factor receptor (EGFR) pathway in many cancer types. More recently, we have been characterising the role of miR-7 in liver cancer, a cancer with increasing global incidence, and have shown miR-7 to be a potent inhibitor of liver cancer cell growth both in vitro and in vivo.

Targeted therapies are taking on a key place in the treatment of human cancer, and in liver cancer the drug called sorafenib is the current standard of care for patients with advanced disease. Although initially successful in suppressing tumour growth in many patients, resistance to the drug is common, leading to recurrence of the disease and widespread metastasis. Hence, identifying ways to overcome abrogate sorafenib resistance and developing new ways to treat liver cancer is a high priority in the field.
This project aims to use a technique called synthetic lethal screening to identify miRNAs that are involved in the rescue of sensitivity to liver cancer cells treated with sorafenib. This will involve screening of a miRNA library for specific miRNAs that rescue sensitivity of liver cancer cells to sorafenib. This would be followed by further studies investigating the functional biology of the miRNA(s) in liver cancer, one or more of which could become additional novel targets for therapy.

This project provides an opportunity to work in the area of microRNAs and cancer in a laboratory with a strong track record in the functional biology of these molecules, perfect a technique that involves cutting edge technology and identify novel regulators of therapeutic resistance (arguably one of the highest priority areas in cancer biology today).

Contact
Professor Peter Leedman  - peter.leedman@perkins.uwa.edu.au


Assessing the role of thyroid receptor beta in breast cancer

Research area: Breast Cancer and nuclear receptor activity
Laboratory: Laboratory for Cancer Medicine
Project suitable for: Honours, Masters, PhD
Essential qualifications: BSc in Biological Sciences to do honours, BSc with honours or equivalent for PhD or Masters
Chief supervisor: Professor Peter Leedman
Other supervisors: Dr Shane Colley
Start date: January 2017, or earlier if suitable

Project outline 

Survival for women diagnosed with breast cancer have significantly improved over the past decades. This has come about in part as a result of a better understanding of activities of growth promoting hormone receptors and how to target these during treatment. While endocrine therapies are available for women with estrogen, progesterone and/or Her2 receptor expressing tumours, those who lack these receptors ie are “triple negative (TNBC)” have far fewer options and lower survival. These patients are in need of novel clinical interventions.
Our laboratory has a strong background assessing the role of receptors in breast cancer. We have recently published an association between reduced thyroid receptor beta (TRB) and poorer outcome for breast cancer patients including TNBC patients. More recently, we have shown that in vitro manipulation of TRB levels and/or targeting of the receptor with ligand can reduce breast cancer cell growth. We are continuing this work in a mouse model of breast cancer comparing tumour development in animals with normal levels of TRB with those in which the receptor has been specifically “knocked out” in the breast epithelium. The studies include genome-wide analyses of TRB activity (ChiP-seq//RNA-seq) as well as detailed in vivo imaging of the preclinical cancer model.
A student joining our laboratory will be involved in pursuing our hypothesis that THB is inhibitory to breast cancer development and that patients may ultimately be treated with TRB drugs to inhibit tumour growth. Further, that manipulation of TRB activity may influence cell sensitivity to current chemotherapeutic agents used to treat patients. Interestingly, small molecule activators of TRB are available for clinical use which were developed to reduce cholesterol. They offer significant potential to be repurposed to treat women with TNBC.
Our research utilises a broad range of molecular and cellular techniques, histological assessment and high end in vivo imaging. By using systems and agents that closely model the clinical scenario we aim for our findings to be more quickly translated into improvements in clinical practice.

Contact
Professor Peter Leedman   - peter.leedman@perkins.uwa.edu.au

Dr Shane Colley - shane.colley@perkins.uwa.edu.au




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