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Understanding Cellular Pathways

Lead PI: Prof Terry Johns, Monash University, VIC

Prof Terry Johns 

Research Idea 

Understanding the various cellular pathways that allow tumours to survive and grow will allow us to develop effective strategies for treating patients with brain cancer. 

Problem 

Over the past few decades, there has been little advance in treatments for brain cancer. In particular, high-grade glioblastoma (HGG) is among the most lethal and difficult to treat of all cancers. HGG kills about 1,300 Australians each year, almost the same number as melanoma. The current treatment regimen involves surgical removal, followed by radiation and chemotherapy. This treatment is almost never curative, often because of the widely invasive nature of these tumours (i.e. their ability to spread) and their intrinsic resistance to radiation and chemotherapy. Even with a good response to treatment, the median survival of patients is less than 15 months. This dismal situation highlights the pressing need to identify new therapeutic ‘targets’ and strategies for HGG.  

Solution 

One strategy for treating cancer is to use targeted therapies. Such therapies specifically target signalling molecules that contribute to the growth and/or survival of tumour cells but not normal cells. This approach is in contrast to the use of chemotherapy, which targets molecules that are present in all cells and therefore has substantial side effects. Many targeted therapies are designed to recognise molecules such as proteins on the surface of the cell. Many of these molecules transmit growth and/or survival signals that originate outside the cell to the inside of the cell, where the signals exert their action. An example is the epidermal growth factor receptor (EGFR), which is one of the hallmarks of brain cancer. Therefore, therapeutics that interact with a receptor and thus decrease transmission of the signal should prevent tumour cells from receiving aberrant signals to grow and survive, allowing them to be killed. 

Why Now? 

Recent technological advances are now allowing researchers to study these cellular pathways in environments that closely mimic human brain tumours. With these newly developed tissue culture methods, researchers can grow tumour cells isolated directly from patients with brain cancer. These cells retain the features of the original tumour both in the ‘test tube’ and in animal models of brain cancer. Cell lines generated in this way provide an exceptional platform for discovering innovative therapeutic approaches. My laboratory has access to over 40 such patient-derived cell lines, as well as animal models of HGG based on these cell lines. Collectively, the properties of this unique set of HGG cell lines are consistent with the main subtypes of HGG, allowing us to take into account the diversity of tumours between patients and the diversity of tumour cells within a patient.

Approach 

Overall, the research in my laboratory is aimed at identifying and developing new strategies for treating HGG. Targeted therapeutics offer the potential to effectively treat brain cancer patients while yielding fewer side effects than chemotherapy and radiotherapy. By using companion screening for target molecules, unnecessary treatment of patients could also be avoided. Given the complexity of brain tumour cells, it is likely that these therapeutics will need to be used in combination to target multiple pathways simultaneously. 

We are focusing on six strands of research:

  • Developing novel antibodies that target key receptors (e.g. EGFR) in cellular signalling pathways that are crucial for HGG growth and invasion.
  • Evaluating novel therapeutics, alone and in combination, for their anti-tumour activity against HGG cell lines and in animal models of HGG.
  • Understanding the signalling mediated by altered forms of EGFR that are commonly found in HGG.
  • Identifying mechanisms that cause resistance to the available EGFR-targeted drugs and designing strategies to reverse this resistance.
  • Determining which signalling networks need to be targeted to achieve robust inhibition of a broad range of HGG tumours.
  •  Providing insight into cross-talk (interactions) between signalling pathways that are important in HG.

Impact 

Overall, this work will lead to new therapeutic strategies to treat HGG, a disease for which there is no effective treatment.

Team & Partners 

Dr Vino Pillay is a postdoctoral researcher in my research group. She is involved in characterising the forms of EGFR that are present in our patient-derived HGG cell lines and investigating their responsiveness to promising EGFR-targeted drug candidates. Dr Jacqueline Donoghue, also a postdoctoral researcher, is applying some of the strategies discussed above to develop therapeutics against a childhood brain cancer called diffuse intrinsic pontine glioma (DIPG). 

The brain tumour research in my laboratory forms an integral part of the Brain Cancer Discovery Collaborative (BCDC), a nationwide team of brain cancer researchers and clinicians that I direct. International collaborators include Profs Web Cavenee, Frank Furnari and Paul Mischel (Ludwig Institute for Cancer Research, San Diego, California) and Dr Tim Adams (CSIRO, Melbourne). My laboratory also works with several pharmaceutical companies, giving my team access to novel targeted therapeutics.

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