Gene Regulation Achievements, Awards & Prizes

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Gene Regulation Achievements, Awards & Prizes - Research at Peter Mac

Recent Awards and Prizes

Adrian Wiegmans

Poster Prize, Lorne Cancer Conference, 2008.

Nicole Messina

Cancer Research Institute Pre-doctoral Scholarship, 2008. Poster Prize, Australian Society of Immunology Annual Meeting, 2008.

Jake Shortt

Leukaemia Foundation PhD Scholarship, 2008.

Recent Research Achievements

MECHANISMS OF ACTION OF HDAC INHIBITORS (HDACi). Our studies on HDACi have utilised highly sophisticated genetic models of human cancer. Using these pre-clinical models we have identified key proteins necessary for the apoptotic and therapeutic activities of HDACi. Moreover, we have demonstrated that tumour cells, but not isogenically matched normal cells are specifically killed by HDACi. Using microarray gene expression profiling we have identified apoptosis-regulatory genes that are specifically regulated in tumour but not normal cells providing a molecular basis for the tumour cell-selctive effects of HDACi. These important mechanistic studies have provided unique insight into the mechanisms of action of structurally diverse HDACi and identified the genetic lesions that can impart resistance to HDACi-mediated therapy. COMBINATION STUDIES USING HDACi. We have quickly recognised that HDACi may be best utilised in the clinic in combination with other agents and we have initiated studies to determine the effects of combining HDACi with antagonists of pro-survival Bcl-2 family proteins such as ABT-737 and Obatoclax and, in collaboration with Prof Mark Smyth, have assessed the effect of combining HDACi with agonistic anti-TRAIL-receptor antibodies. These pre-clinical studies, using genetically engineered mouse models of cancer, have not only provided important information on the therapeutic potential of these combination strategies, but have provided valuable insight into the mechanisms of action of novel anti-cancer agents. GENETIC MOUSE MODELS TO STUDY TUMOUR DEVELOPMENT AND THERAPEUTIC ACTIVITIES OF ANTI-CANCER AGENTS. In collaboration with Drs Smyth and McArthur and our overseas colleagues, we have extended the list of genetically engineered mouse models of cancer currently in use in the lab to include models of acute myeloid leukemia (AML1-ETO), T cell leukemia (Tel-JAK2), multiple myeloma (Vk*Myc), diffuse large B cell lymphoma (Im-Bcl6), breast carcinoma (Her2/neu) and prostate carcinoma (TRAMP). We have used these models to assess the therapeutic activities of HDACi, and agonistic anti-TRAIL antibodies combined with other therapeutic antibodies directed against oncogenic targets such as Her2. Moreover, we are determining the role of immune cells and effector molecules in regulating the development and spread of these tumours in order to assess the potential immunosurviellence effects in these models. FUNCTIONAL GENOMICS-BASED STUDIES TO IDENTIFY NOVEL TUMOUR SUPPRESSOR GENES AND GENES THAT REGULATE CHEMOTHERAPEUTIC DRUG ACTIVITIES. In collaboration with Drs McArthur, Pearson and Hannan, we have initiated whole genome, functional genomics-based studies utilising the sophisticated RNA interference technology available from the Victorian Centre for Functional Genomics to identify novel tumour suppressor genes and genes that regulate the apoptotic activities of anti-cancer drugs. We have utilised advanced human cell lines developed by Prof. Robert Weinberg that were derived from primary breast epithelial cells and forced to go through stages of malignant transformation through the step-wise introduction of four different genetic elements (SV40 large and small T, hTERT, mutant/active Ras). Pre-malignant breast cells are being utilised to identify new tumour suppressor genes, and the fully transformed breast cells are being used to identify genes necessary for apoptosis induced by vorinostat and other anti-cancer agents. FUNCTIONAL CROSSTALK BETWEEN TYPE I AND II INTERFERON. It has been known for some time that exposure of cells to type I interferons (interferons a and b) “primes” those cells to respond rapidly and robustly to other cytokines such as type II interferon (interferon g). Until now, it has been unclear how these two different signaling pathways communicate, however recent work from our laboratory has identified a key molecular event that underpins this process. We have demonstrated that small ‘priming’ quantities of type I interferon enhance cellular responses to IFNγ by maintaining basal levels of STAT1, a key transcription factor necessary for the activation of cellular genes necessary to mediate a cellular response to type II interferon.