PhD Candidate, The University of Sydney
Melanoma is one of the most aggressive and treatment-resistant human cancers, having increased radically worldwide during the past several decades in the Caucasian population. With an overall mortality rate of around 20%, it is responsible for the 80% of skin cancer-related deaths worldwide, which is largely due to its propensity to metastasize to other organs. In fact, metastatic melanoma is the 4th most common cancer in Australia and the 6th most common cancer in the USA. Although early-stage melanoma can be effectively treated with surgery, metastatic melanoma is highly resistant to conventional therapies.
Unfortunately, the annual incidence rates of melanoma worldwide are increasing rapidly each year, and at a greater rate than any other major cancer. According to recent studies, 1- and 2- year survival rates in patients with metastatic melanoma were ~25% and 10%, respectively, with a median overall survival of 6 months.
My project investigates major drivers and key molecular pathways involved in melanoma progression, and some have been the subject of recent pharmacological strategies to treat this belligerent disease. These investigations underpin the development of new treatments and prognostic markers for melanoma by providing significant new information on the biological and inter-connected functions of those molecular players in this disease.
Abstract: The outgrowth of metastatic and therapy-resistant subpopulations in cancer remains a critical barrier for the successful treatment of this disease. In melanoma, invasion and proliferation are uncoupled, such that highly proliferative melanoma cells are less likely to be invasive, and vice versa. The transition between each state is likely a dynamic rather than a static, permanent change. This is referred to as "phenotype switching". Wnt signaling pathways drive phenotypic changes and promote therapy resistance in melanoma, as well as play roles in the modulation of the immune microenvironment. Three Wnt signaling pathways play a role in melanoma progression, canonical (β-catenin dependent), polar cell polarity (PCP), and the Wnt/Ca²⁺ pathway. Here we summarize phenotype plasticity and its role in therapy resistance and immune evasion. Targeting the Wnt signaling pathways may be an effective way to overcome tumor plasticity in melanoma.
Pub.: 08 Nov '15, Pinned: 31 Aug '17
Abstract: Melanoma is one of the most aggressive forms of skin cancer. Furthermore, incidence rates are increasing. Until recently, no agent had been shown to improve survival over supportive care and treatment guidelines recommended that patients with metastatic disease were entered into clinical trials. With so few treatment options available, there was a clear need for new, more effective treatments in this setting. Melanoma serves as a 'model' tumour for understanding immunity to cancer. Melanoma tumour-associated antigens were among the first cancer antigens to be identified and classified, with further studies showing that many of these are also expressed by other tumour types. In addition, melanoma regression has been associated with vitiligo, visibly confirming an active role of the immune system in this type of cancer, and spontaneous regression of primary melanomas has also been observed in some cases. These observations, relating to the activity of the immune system in melanoma, provided strong evidence that this tumour would be amenable to immunotherapy, with immunotherapies such as cytokines, adoptive cell transfer and T-cell modulators shown to be an effective therapeutic approach. Against this background, melanoma has long been at the cutting edge of immuno-oncology research and will likely continue to be used as a model tumour to increase our understanding of immuno-oncology and to inform development in other types of cancer.
Pub.: 29 Aug '12, Pinned: 31 Aug '17
Abstract: Melanoma has markedly increased worldwide during the past several decades in the Caucasian population and is responsible for 80% of skin cancer deaths. Considering that metastatic melanoma is almost completely resistant to most current therapies and is linked with a poor patient prognosis, it is crucial to further investigate potential molecular targets. Major cell-autonomous drivers in the pathogenesis of this disease include the classical MAPK (i.e., RAS-RAF-MEK-ERK), WNT, and PI3K signaling pathways. These pathways play a major role in defining the progression of melanoma, and some have been the subject of recent pharmacological strategies to treat this belligerent disease. This review describes the latest advances in the understanding of melanoma progression and the major molecular pathways involved. In addition, we discuss the roles of emerging molecular players that are involved in melanoma pathogenesis, including the functional role of the melanoma tumor antigen, p97/MFI2 (melanotransferrin).
Pub.: 05 Feb '16, Pinned: 31 Aug '17