Drug Discovery

Staff
Funding
Collaborators
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Key Publications
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Lab Head: Dr Peter Parsons
peterP@qimr.edu.au

Skin cancers are the most expensive cancer to treat in Australia because there are so many of them. We want to find out what ultraviolet light does to cells in the skin, and how the cancers start. This information might be useful in preventing them. Similar information about molecular changes in normal and cancer cells is helping us develop new drugs for treating these and other types of cancer.

The overall theme is to identify and study the function of genes that are important in the development and treatment of melanoma. Such information might help us understand the peculiar epidemiology of melanoma and suggest new forms of therapy. The wide range of techniques being used includes transcription profiling with cDNA microarrays. There is collaboration with molecular biologists for cloning genes of interest and with epidemiologists, chemists and clinicians for application of the results.

Recent achievements include discovery of MIC-1 as a new cytokine associated with the induction and progression of melanoma, first demonstration of the tumour selectivity of histone deacetylase inhibitors in vitro and in vivo, and identification of the molecular target for new compounds being trialled for the topical treatment of non-melanoma skin cancer.

Some of the special technologies in use within this laboratory can be accessed by external organisations on a commercial basis.

Role of MIC-1 in the acute response to solar UV and in progression of human melanoma
A new and more realistic method of UV irradiation of cultured cells combined with cDNA microarray screening led to identification of MIC-1 as a new factor in solar UV signalling and melanoma progression. Expression of MIC-1 is minimal in melanocytes and primary melanomas but strong in metastatic melanomas, suggestive of a progression mechanism related to cytokine action. MIC-1 was found to be induced in normal cells of the skin by solar UV. Some squamous and basal cell carcinomas were also found to express MIC-1. This opens several new avenues of investigating cell signaling pathways in UV-induced tumors. Together with gene expression profiling of peripheral lymphocytes, evidence for systemic induction of gene expression in the epidermis following sun exposure and development of a quantitative PCR assay for mutation in skin, we have a range of tools for dissecting the molecular epidemiology of skin neoplasms.

Discovery of prognostic and progression markers in head and neck and ovarian cancer
Extensive analysis of fresh tumor and relevant normal tissue by expression profiling of the mRNA of up to 40,000 genes with DNA chips has revealed many candidates of potential interest as markers for the management of patients and as targets for therapy. Some of these genes have been validated at the protein level, and are better indicators of outcome than the available clinical parameters. Others seem to be important in the progression from normal to the tumor state, and functional validation is now being sought by manipulating their expression in cultured tumor cells.

Discovery and development of natural products active against human cancers
Purification and preclinical evaluation is being carried out of natural products in collaboration with EcoBiotics. A range of test systems are in use, and the mechanism of action of lead compounds is investigated.

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Staff

Funding

NHMRC
EcoBiotics Ltd

Collaborators

• Prof. Adele Green, QIMR
• Dr Nick Hayward, QIMR
• Dr Rick Sturm, Institute of Molecular Biosciences, UQ
• Dr David Fairlie, Institute of Molecular Biosciences, UQ
• Dr Sam Breit, St Vincents Hospital, Sydney

Projects for Students

The Melanoma Genomics Group has a number of projects available for students.

Key Publications

Cozzi, S-J., Parsons, P.G., Ogbourne, S.M., Pedley, J. and Boyle, G.M. (2006) Induction of senescence in diterpene ester-treated melanoma cells via PKC-dependent hyperactivation of the MAPK pathway. Cancer Res. 66, 10083-91. [pubmed abstract]

Newton, T.R., Parsons, P.G., Lincoln, D.J., Cummings, M.C., Wyld, D.K., Webb, P.M., Green, A.C. and Boyle, G.M. (2006) Expression profiling correlates with treatment response in women with advanced serous epithelial ovarian cancer. Int. J. Cancer. 119, 875-883. [pubmed abstract]

Widyarini, S., Allanson, M., Gallagher, N., Walker, C., Pedley, J., Boyle, G.M., Parsons, P.G., Whiteman, D.C. and Reeve, V.E. (2006) Isoflavonoid Photoprotection in Mouse and Human Skin is Dependent on Metallothionein. J. Invest. Dermatol. 126, 198-204. [pubmed abstract]

Boyle, G.M., Martyn, A.C. and Parsons, P.G. (2005) Histone deacetylase inhibitors and malignant melanoma. Pigment Cell Res. 18, 160-166. [pubmed abstract]

Ogbourne, S.M., Suhrbier, A., Jones, B., Cozzi, S-J., Boyle, G.M., Morris, M., McAlpine, D., Johns, J., Scott, T.M., Sutherland, K.P., Gardiner, J.M., Le, T.T.T., Lenarczyk, A., Aylward, J.H. and Parsons, P.G. (2004) Anti-tumor activity of 3-ingynel angelate: Plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res. 64, 2833-2839. [pubmed abstract]

Challacombe JM, Suhrbier A, PARSONS PG, Jones B, Hampson P, Kavanagh D, Rainger GE, Morris M, Lord JM, Hoang-Le D, Le T, Ogbourne SM. Neutrophils are a Key Component of the Anti-tumor Efficacy of Topical Chemotherapy with 3-Ingenyl Angelate. J. Immunol. 2006; 177:8123-32. [pubmed abstract]

Kahnberg P, Lucke AJ, Glenn MP, Boyle GM, Tyndall JD, PARSONS PG, Fairlie DP. Design, synthesis, potency, and cytoselectivity of anticancer agents derived by parallel synthesis from alpha-aminosuberic acid. J Med Chem. 2006; 49:7611-22 . [pubmed abstract]

Chin, D., Boyle, G.M., Theile, D.R., PARSONS, P.G. and Coman, W.B. The human genome and gene expression profiling. J. Plast. Reconstr. Aesthet. Surg. 2006; 59: 902-911.[pubmed abstract]

Cook, A.L., Boyle, G.M., Leonard, J.H., PARSONS, P.G. and Sturm, R.A. BRN2 in Melanocytic Cell Development, Differentiation and Transformation. In "Melanocytes to Melanoma: The Progression to Malignancy" pp 149-168 by Humana Press Ed Hearing, V.J. and Leong, S.P.L. 2006.

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