Olivia Newton-John Cancer Research Institute (LTU School of Cancer Medicine) Research Scholarships

The Olivia Newton-John Cancer Research Institute (ONJCRI), based at the Austin Hospital in Melbourne, is the La Trobe University School of Cancer Medicine. ONJCRI are currently have a number PhD scholarships available within their research programs.

As a graduate researcher with ONJCRI you will have access to a wide range of resources, services and academic programs. You can join our institute and study with renowned scientists with excellent publication records who are committed to helping you build a successful career in translational cancer research. Their translational research approach means that every day you’ll be able to work alongside clinicians, collaborating in the laboratory and at the bedside, to develop breakthrough therapies to help people feel better, sooner.

Currently the ONJCRI is offering three specific scholarships (see projects below) for outstanding PhD candidates who have completed honours or masters by research in molecular biology, biochemistry or biomedical sciences.

If these projects do not align with your area of research interest, take some time to look over https://www.onjcri.org.au/our-research/#index ONJCRI are always on the search for more brilliant postgraduate scientists to join their research programs.

SCHOLARSHIP PROJECTS:

Improving responses to immunotherapy (ONJ-23001)

Immunotherapy has reshaped the way we treat cancer. However, obstacles still exist including the inability to predict treatment efficacy, patient response and the development of resistance. Utilising the expertise of our joint labs in cancer immunology (Kearney) and membrane trafficking pathways (Lee/Fairlie), this PhD project will employ targeted CRISPR-based screening technologies to identify mechanisms that sensitise or inhibit tumour cells to T cell-mediated killing. For this project, the PhD candidate will utilise and develop skills in advanced molecular biology (in particular CRISPR screens), cell biology, membrane trafficking and cancer immunology.

Supervisors: Dr Doug Fairlie, Dr Conor Kearney, Dr Erinna Lee

For further information please contact: Doug Fairlie

Choosing the right T cell for CAR therapy approaches (ONJ-23002)

Chimeric Antigen Receptor (CAR) T cells have shown clinical success in hematological cancers with multiple therapies approved around the world. However, no similar success can be reported for the treatment of human solid tumours. Multiple strategies have been suggested to overcome the issues related to treatment failure in this setting including poor T cell infiltration and a suppressive tumour microenvironment (TME) affecting CAR T cell efficacy.

T cell subset heterogeneity has been characterized in depth over the last decade, however direct head-to-head comparisons between vastly distinct classes of T cells and their utility for CAR T cell approaches have not been performed. Critically, beyond CD4 and CD8 classical T cells, non-conventional T cell subsets such as MAIT and T cells have higher organ-homing capacity and migrate preferentially to nonlymphoid tissue, where they can react rapidly to stimulus. Here, we hypothesise that MAIT cells and T cells may have several advantages over conventional T cells including their potential to be utilized in a third-party manner when generated from healthy donors and their increased cytotoxic capacity relative to conventional CD4 and CD8 T cells. Thus, we aim to holistically explore these T cell subsets and their propensity to act as CAR T cell therapeutics in the setting of solid tumours.

For this we will generate CD4, CD8, MAIT and T cell subsets expressing CARs of the same specificity and test their ability in parallel for in vitro cytotoxicity and cytokine secretion against tumour cells utilizing 2D and 3D cell culture models .We will identify the best layout of CAR constructs for armoured CAR approaches (activation domains and cytokine secretion) for the various T cell subsets and compare their in vivo ability to infiltrate and target solid tumours in mouse models. Within in vivo experiments, we will also exploit the amenability of unconventional CAR T cells as they can be selectively activated and expanded with TCR agonists such as antigens to enhance cell numbers or overall therapy persistence. In addition, we will utilize CRISPR-Cas9 technology to specifically override candidate molecules contributing to the immune-suppressive state of our generated CAR T cells (e.g. PD-1KO T cells) via approaches that have already been optimized within the host laboratories (Ref Giuffrida et al. 2021, Nature Communications).

The project will take place across 3 of Melbourne’s leading cancer and immunology institutes (PeterMac/PDI/ONJCRI) with lab rotations amongst these, leveraging the developed methodologies and expertise in these laboratories in unconventional T cell biology, cancer immunology, and CAR T cell development.

Supervisors: Associate Professor Andreas Behren, Associate Professor Paul Beavis (PMCC), Dr Fern Koay (PDI)

For further information please contact: Andreas Behren

Tuft Cells in the GI Cancer Microbiome: Unraveling their role in Microbial Regulation (ONJ-23003)

Until recently, it was common to think that tumours are simply masses of a patient’s own cells that malfunction and grow uncontrollably when they, in fact, are communities of many different cell types. New research has now shown that tumours also play hosts to a collection of other life-forms entirely – microorganisms such as bacteria and fungi, some of which thrive in the environment around the tumour while others live inside the tumour cells themselves. Until recently it was unknown what roles these microbes play in tumours, however novel findings show that they can either assist or oppose tumour development and progression. For example, bacteria can protect the tumours by inactivating chemotherapy drugs or altering the ability of the immune system to target and destroy tumour cells, while other bacteria protect the body from tumour growth by detoxifying carcinogens or reducing levels of harmful reactive oxygen molecules that can damage DNA. This area of cancer microbiology is an emerging and exciting topic of research and promises to lead to new approaches for treating and preventing cancers.

Tuft cells (TCs) are a rare chemosensory epithelial cell type in the gastrointestinal (GI) tract and sole source of epithelial interleukin (IL) 25. TCs have an important function as immune sentinels in the epithelium that relay danger signals to the mucosa-resident immune cells in order to maintain a healthy tissue. Recently, TCs were shown to detect the presence of certain microbial metabolites and to induce the expression of IL13 in cells of the innate immune system which in turn altered the expression profile of antimicrobial peptides (AMPs) in epithelial cell types such as Paneth and goblet cells which led to changes in the composition of the mucosal microbiota. Moreover, treatment of mice with IL25 alone was sufficient to induce similar changes to the microbiota in the absence of microbial metabolites. Thus, TCs can sense and regulate the makeup of the resident microbial communities.

The aim of this PhD project is to investigate whether TCs inside or outside of the tumour tissue are involved in the regulation of the tumour-associated microbiota. We will use preclinical GI tumour models where we can specifically ablate TCs either in the tumour or in the unaffected surrounding healthy tissue and determine the abundance and composition of microbial communities by 16S RNA sequencing. We will further complement these experiments by pharmacologically blocking the activity of IL25 and IL13 in vivo. Lastly, we will determine the impact of both genetic and pharmacologic approaches on the ability of the host immune system or chemotherapy treatments to limit tumour growth.

This project will use various techniques including, but not limited to, flow cytometry, immunofluorescent microscopy and 16S RNA sequencing. The project will provide the candidate with the opportunity to work in cancer microbiology, an emergent and exciting new area of cancer research. Basic training in immunology/microbiology or cancer biology (Honours or Masters minimum) will be required.

Supervisors: Associate Professor Michael Buchert, Professor Matthias Ernst

For further information please contact: Michael Buchert

Breast Cancer Dormancy – Mechanisms and Development of Rational New Therapies (ONJ-23004)

In Australia, over 3000 women die from breast cancer each year, and worldwide, over 520,000 women will die. Their cause of death is nearly always uncontrollable secondary tumours, or metastases. Distant metastatic disease is detected in up to 20% of those diagnosed with breast cancer, ultimately resulting in their death. Cancer relapse can occur years or decades after the initial diagnosis and treatment, causing ongoing fear and anxiety for patients.

It is evident that disseminated tumour cells (DTC) can remain in a clinically undetectable dormant state for years before causing a relapse. Since many types of chemotherapy rely on disrupting cell division, tumour cells in a dormant state are resistant to such therapies. To prevent recurrences and reduce breast cancer deaths, we need therapies that can either minimise release from dormancy or completely eradicate dormant cells. Indirect evidence for the existence of residual disease in patients comes from detection of circulating tumour cells (CTCs) or cell-free tumour DNA in blood samples. The difficulty of directly detecting and analysing residual disease in patients, in combination with the challenges of modelling dormancy in the laboratory has resulted in only fragmented knowledge of the establishment of DTCs in distant organs and their outgrowth into metastases.

The aim of this project is to use our preclinical models of breast cancer dormancy to image and isolate cells in the dormant cell niche in bone and lung and to generate transcriptomic profiles of both tumour cells and the surrounding host cells. With this knowledge, we will assess the efficacy of therapies designed to maintain tumour dormancy or target a dormancy-specific vulnerability to eradicate these cells. We will use mouse-based breast cancer models that naturally display dormancy to image and investigate the tumour cell niche in mice using confocal and multiphoton microscopy. Tumour cells will be recovered for transcriptomic profiling as a basis for testing different therapies designed to either maintain dormancy of disseminated tumour cells or to specifically target dormant cells.

Supervisors: Professor Sarah Ellis, Professor Robin Anderson

For further information please contact: Sarah Ellis

Benefits of the scholarship include:

• a stipend for up to three and a half (3.5) years for doctoral candidature, with a value of $33,500 per annum (2023 rate)
• a tuition fee scholarship for up to four (4) years for doctoral candidature. Successful domestic applicants will be awarded an RTP Fees Offset scholarship and successful international applicants will be awarded a La Trobe Full Fee Research Scholarship (LTUFFRS) unless another tuition support scholarship exists
• relocation allowance and publication/thesis allowance
• opportunities to work with La Trobe’s outstanding researchers, and have access to our suite of professional development programs.