Dr Natalie Lister - Prostate Cancer Group Leader

I personally have known two family members diagnosed with prostate cancer. The first was diagnosed with localised prostate cancer and was successfully treated via surgical removal of his prostate. The second, however, was diagnosed with prostate cancer that had already metastasized. As he begins his journey with androgen deprivation therapy, I am aware that there are currently no personalized treatment options approved for prostate cancer patients. Ultimately, he will run out of therapeutic options. This has focused my research efforts to advance prostate cancer research to, not only extend patient survival, but provide targeted therapies tailored to patients on an individual basis.

My innovative research program exploits the addiction of cancer cells to essential gene regulatory networks that are controlled by dominant, and predictable core sets of transcription factors, regardless of their underlying oncogenic drivers. Using this approach, we have successfully demonstrated that computational netowork algorithms can predict the transcription factors which regulate the ‘oncogenic network’ of metastatic prostate tumour cells and reveal novel network vulnerabilities for targeted therapy. Moreover, we extrapolate these network signatures into small molecule compounds which we demonstrate could effectively kill prostate tumour cells.

Working closely with oncologists and the Australian and New Zealand Urogenital and Prostate Cancer (ANZUP) trails group we aim to translation our findings into the clinical to provide targeted therapy for men with lethal prostate cancers. 

Unmet patient need: New treatment options for men with drug-resistant prostate cancer

Preclinical models are essential tools for research translation and form the foundation my research program.

The majority of drugs which have demonstrated preclinical efficacy, fail to provide real clinical benefit. This is partly due to the limitations of immortalized cell-lines to reflect primary tumour specimens. Human prostate tumours are notoriously difficult to grow in the laboratory. To overcome this problem, my work has contributed to the establishment of >30 new preclinical models of human prostate cancer, including xenografts and organoids, from men who are currently living with, or who have recently died from lethal prostate cancer. These patients have often progressed, despite multiple lines of anti-cancer therapies and have few available treatment options. Our cohort contains multiple sup-types of prostate cancer, including rare neuroendocrine tumours with aggressive disease pathology and metastasis from soft-tissues and organs – two features with emerging clinical incidence.  These tumours are often refractory to multiple drugs and progress rapidly, reflecting the current state of clinical practice. Our new prostate tumour PDX platform provides the unprecedented opportunity to, not only predict novel network targets of contemporary disease, but to validate these targets in matching patient-specimens (as opposed to non-specific and immortalized prostate tumour cell lines established decades ago).

Identification of new transcriptional network targets for men with lethal prostate cancers

The androgen receptor (AR) is a transcription factor that regulates active gene networks in prostate cancer. For nearly 80 years¹, researchers and clinicians have worked to suppress androgen signaling (also known as castration therapy) in the hope of curing prostate cancer. However, despite increasingly potent AR-directed therapy, castrate-resistant prostate cancer remains incurable. It is clear that alternate therapeutic targets, beyond the AR, are required to provide new treatment options for patients and their families.

In the past, to find new druggable cancer targets, researchers have mainly focused on key pathways enriched in tumours (e.g. the hormone axis in prostate cancer) or classic oncogenes highly expressed across a large proportion of patient tumours. However, it has long been appreciated that tumour cell signaling networks, like normal cells, are controlled by dominant and predictable sets of transcription factors, known as master regulators. These master regulators may not be the ‘top hits’ in conventional gene expression analysis, but network modelling has revealed their powerful control of local gene regulation, including the AR gene network.  

My work harness the power of master regulator-derived signatures to focus efforts to improve targeted therapy by identifying the most relevant gene networks, as opposed to simply the most ‘abundant’ gene networks identified through conventional gene set enrichment analysis. Following this rationale, I have created a core gene network profile for candidate transcription factor that have been identified as critical for aggressive prostate tumours. Core gene signatures are then used to search for drugs capable of disrupting these ‘master’ networks through Connectivity Map databases.

Our novel empirical-computational pipeline opens a new stream of in silico target discovery for lethal prostate tumours with few available treatment options. Ultimately, we envision these findings can be translated into any cancer cell, to generate new and previously overlooked therapeutic targets on a patient-by-patient basis. Our work opens a window into personalised medicine, in the future we not only could screen in vitro for different targets but we could predict these targets from an initial tumour biopsy on a patient by patient basis.

Tutor- Immunology 3031

Guest Lecturer Immunology 3031/41

As a scientist, I am passionate about promoting STEM to raise awareness in young women and men of our community. To this end I am a participant in ‘Girls day Australia’ an initiative with the Goethe Institute to promote STEM careers to aspiring female high-school students across Victoria (www.goethe.de/australia.girlsday). In addition, I am a part of the annual class presentation at Cranbourne Secondary College. Here I present my work as a research scientist to students and discuss possible scientific career paths.

As a member of the Prostate Cancer Research Group, we organize laboratory visits for patients and their families to disseminate and discuss our latest research. In doing so, I communicate my latest research findings and seek their feedback. I find this is a great way to engage with the patients and their families and increase the awareness of prostate cancer research in the community and beyond. I have been invited to present my work at the Prostate Cancer Foundation of Australia (PCFA) – Biggest Bloke’s Lunch as well as local prostate cancer support groups (Ringwood branch).