One-in-seven men will be diagnosed with prostate cancer (PC) in their lifetime and PC related deaths are >3000 per year in Australia. Despite approaches such as surgical removal of the prostate, radiation therapy and androgen deprivation, many patients develop advanced cancers, which inevitably acquire resistance to castration levels of testosterone; this most aggressive state is referred to as castration-resistant prostate cancer (CRPC). In an increasing subset of PC patients, androgen receptor (AR)-targeted treatment selection pressure leads to the emergence of CRPC with neuroendocrine features. Indeed, the prognosis of patients with neuroendocrine differentiated prostate cancer (NEPC) is poor due to inherent resistance to conventional AR-directed therapies. Consequently, new therapeutic strategies for CRPC, and especially NEPC, are critical to improve patient outcomes, and will likely require combination therapies to better target tumour heterogeneity.
Targeting tumour heterogeneity in prostate cancer through inhibition of “housekeeping” cellular functions with a focus on mRNA translation machinery
Identification of novel combination therapy with emphasis on protein synthesis and/or ribosome biogenesis inhibition
Identification and validation of novel “theranostic” targets to image and treat prostate cancer
Identification of circulating tumour DNA (ctDNA) biomarkers of treatment response and disease progression
Deregulated protein synthesis as a therapeutic vulnerability in prostate cancer
Cancer is characterised by aberrant cell proliferation and survival. A key requirement for neoplastic growth is increased protein synthesis (mRNA translation). Dysregulation of mRNA translation is common in cancer and multiple oncogenes (e.g. MYC, RAS and PI3KCA) and tumour suppressors (e.g. PTEN, LKB1, TSC1/2 and p53) impinge on the translation apparatus. Efficiency of translation is determined by cis- (e.g. 5’ and 3’ untranslated regions (UTR), upstream open reading frames (uORFs), codon composition) or trans-acting factors (e.g. initiation factors, elongation factors, transfer RNA (tRNA)). In addition to global increase in protein synthesis, cancer cells translate subsets of mRNAs with altered efficiency as compared to normal cells. Recent studies, including our work, suggest posttranscriptional enzymatic modifications on specific tRNA nucleosides as required for proliferation in cancer cells. tRNAs can undergo enzymatic modifications at multiple positions, but modifications of the first base of the anticodon (position U34) by a group of enzymes (ALKBH8, CTU1/2 and the ELP complex) can have drastic impact on translation efficiency. We hypothesise that alterations in U34 tRNA modifications orchestrate the translational reprogramming required for cancer progression and inhibition of U34 modifying enzymes is a new therapeutic avenue in prostate cancer.
Inhibition of ribosome biogenesis to treat advanced prostate cancer
In this project we will determine if small molecule inhibitors targeting the tumor’s cellular machinery responsible for making proteins (called ribosomes) alone or in combination with a drugs and/or radioligand targeting the tumor’s genetic material will be efficacious in PC, especially the aggressive forms CRPC and NEPC. As our approach is independent from the targets of current standard of care in PC, it could be used in combination for patients with CRPC.
Developing novel ligands for prostate cancer theranostics applications (Supervisors: Dr Haskali, Dr Furic)
Theranostic treatment for prostate cancer involves using a radioactive molecule to reveal the cancer’s spread via a positron emission tomography (PET) scan and then a similar radioactive molecule to kill the cancer cells. We have identified new potential targets which could be used to treat advanced metastatic prostate cancer. In this project we plan to design small peptide which specifically bind to the novel targets with high affinity.
Biomarker identification in lutetium PSMA-treated prostate cancer patients using circulating tumour DNA (A/Prof Arun Azad, Prof Michael Hofman, Dr Luc Furic)
Prostate-specific membrane antigen (PSMA) is a type 2 membrane glycoprotein overexpressed on prostate cancer cells that has emerged as a key therapeutic target in metastatic castration-resistant prostate cancer (mCRPC). Two landmark trials (including one led by Peter MacCallum Cancer Centre) have positioned lutetium PSMA radionuclide therapy (Lu-PSMA) as a highly effective new treatment option for mCRPC. Nevertheless, responses to Lu-PSMA treatment can be variable, and development of resistance remains inevitable. Identifying biomarkers linked to outcomes with Lu-PSMA is therefore a critical unmet need, in order to select patients most likely to benefit from treatment and to dissect mechanisms of therapeutic resistance.
As part of the newly opened Prostate Imaging and Theranostic Centre of Excellence (ProsTIC), we are running a series of investigator-led clinical trials with Lu-PSMA and other theranostics. Serial plasma samples collected as part of these trials represents a valuable world-first repository of biospecimens with which to perform biomarker discovery. Currently, these plasma samples are being utilised to generate targeted sequencing data from which somatic and germline mutations can be identified. As part of this fully-funded project, students will help to develop bioinformatics approaches to analyse and explore next-generation sequencing data to identify putative predictive and prognostic biomarkers for this novel radionuclide therapy that may be incorporated into future clinical trials here at Peter Mac. Students will receive training in clinical trial research, genomics, cancer biology, bioinformatics and biostatistics and will work with a team of wet-lab biologists and bioinformaticians. The candidate will require prior experience with unix-like operating systems, R and/or python programming languages. A background in mathematics or statistics is also highly desirable.
Recruiting PhD/MSc candidates