Cancer Genetics and Genomics Projects

Cancer Genetics and Genomics Projects - Research at Peter Mac

Involvement of siah proteins in the tumour/stroma microenvironment

Supervisors: Prof David Bowtell & Dr. Andreas Moeller

Tumours interact with their surrounding stroma in several ways to enable the tumours to grow and eventually metastasise. Understanding the interaction of tumour cells with surrounding stroma in the tumour microenvironment is crucial to therapeutically target tumour progression. One of the key hurdles of tumour growth is to initiate the outgrowth of new blood vessels (neo-angiogenesis). The new tumour-associated blood vessels supply the tumour with oxygen and nutrients as well as enable its spread to distant organs via the blood stream. A key signal for the induction of neo-angiogenesis is low oxygen levels (hypoxia) in the tumour mass. On a cellular level, hypoxia causes the production and secretion of factors like VEGF, which in turn induce neo-angiogenesis.

Our group has established several breast cancer models and is investigating signal transduction in the tumour microenvironment. We have identified key enzymes that regulate the hypoxic response and we are examining their impact on neo-angiogenesis. We are currently developing drug-like molecules to some of these enzymes and are studying their efficacy in vitro and in vivo.

We are now looking for motivated students (both Honours and PhD students) to strengthen our group. The projects will investigate the communication between tumour cells and their surrounding tissue. Especially the projects will focus on neo-angiogenic signals as well as immune modulator signalling. The projects are utilizing unique knockout and transgenic tumour systems and are supported by excellent mouse breeding and molecular/biochemical facilities and will be performed as part of an internationally competitive multidisciplinary team, incorporating a number of modern techniques such as microarray, quantitative real-time PCR, protein degradation assays and siRNA approaches.

For more information about this project contact:

Professor David Bowtell

+61 (0)3 9656 1356

david.bowtell@petermac.org

Dr Andreas Moeller

+61 (0)3 9656 1356

andreas.moeller@petermac.org

Analysis of candidate genes in acquisition of chemoresistance in ovarian cancer

Supervisors: Prof David Bowtell & Dr Prue Cowin

Ovarian cancer is the 5-6th most common cause of cancer death in women in Western countries, with ~800 deaths per year in Australia, with high-grade serous ovarian cancers accounting for the majority of deaths (>60%). Standard first-line chemotherapy involves a platinum agent (typically carboplatin) and a taxane. Whilst most women respond well to first line treatment, the disease typically recurs and, following treatment with multiple agents, acquired resistance develops followed by progression and death, usually within 5 years of initial diagnosis.

We are part of the Australian Ovarian Cancer Study (AOCS), one of the largest ovarian cancer cohort studies in the world. We are also one of the two Australian projects funded through a $27 million NHMRC grant to participate in the International Cancer Genomics Consortium (ICGC). The proposed studies involves the comparison of ovarian tumour tissue collected at the time of primary surgery with samples from the same women following disease recurrence to investigate genes changes linked to acquired drug resistance and recurrent disease. Studying disease recurrence using a paired-sample approach lends considerable power to analysis.
A number of genes have been linked with acquired chemoresistance in ovarian cancer, including GSTπ (Ikeda et al 2003; van der Zee et al 1995), ATP7a and ATP7B Nakayama et al 2002, 2004). Data for the copper transporter ATP7a is amongst the most compelling, where expression in primary cancer samples is associated with poor outcome.

This project aims to test literature-derived candidate genes in paired samples to determine if they are associated with acquired platinum resistance. Expression levels of candidate genes will be measured by Q-PCR and IHC on TMA, and findings related to clinical outcome. There is also increasing evidence that hypermethylation of the promoter of the mismatch repair gene hMLH1 is responsible for increased resistance observed in cancer cells. To validate the methylation status of hMLH1 in primary and relapse samples, methylation specific Q-PCR will be performed.
The student will learn key molecular biological techniques and will be exposed to large-scale human genetic studies that are making use of the emerging technologies, including next generation sequencing. The Cancer Genetics and Genomics lab has a very strong reputation in cancer genetics and genomics, and in fundamental studies in cancer cell biology. He/she will have the opportunity to contribute insights into one of the most clinically significant questions in ovarian cancer – the emergence of drug resistance.

For more information about this project contact:

Professor David Bowtell

+61 (0)3 9656 1356

david.bowtell@petermac.org

Dr Prue Cowin

+61 (0)3 9656 1356

andreas.moeller@petermac.org