ORCID Profile
0000-0002-1357-0884
Current Organisation
Peter MacCallum Cancer Centre
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Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-09-2022
DOI: 10.1200/JCO.22.00208
Publisher: Wiley
Date: 14-09-2023
DOI: 10.1111/BJU.16158
Abstract: Salvage radiation therapy and surveillance for low risk PSA recurrence have competing risks and benefits. The efficacy of early salvage radiation therapy to the prostate bed with or without pelvic lymph nodes compared to surveillance in patients with prostate specific antigen (PSA) recurrence following radical prostatectomy and no identifiable recurrent disease evident on prostate specific membrane antigen‐positron emission tomography/computerised tomography (PSMA‐PET/CT) is unknown. Dedicated Imaging Post‐Prostatectomy for Enhanced Radiotherapy outcomes (DIPPER) is an open‐label, multi‐centre, randomised phase 2 trial. The primary endpoint is 3‐year event‐free survival, with events comprising one of PSA recurrence (PSA ≥0.2ng/mL higher than baseline), radiologic evidence of metastatic disease or initiation of systemic or other salvage treatments. Secondary endpoints include patient reported outcomes, treatment patterns, participant perceptions and cost‐effectiveness. Eligible participants have PSA recurrence of prostate cancer following radical prostatectomy, defined by serum PSA 0.2‐0.5ng/mL, deemed low risk according to modified European Association of Urology (EAU) biochemical recurrence risk criteria (ISUP Grade Group ≤2, PSA doubling time more than 12 months), with no definite robable recurrent prostate cancer on PSMA‐PET/CT.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-03-2022
DOI: 10.1200/JCO.21.00941
Abstract: We previously reported that enzalutamide improved overall survival when added to standard of care in metastatic, hormone-sensitive prostate cancer. Here, we report its effects on aspects of health-related quality of life (HRQL). HRQL was assessed with the European Organisation for Research and Treatment of Cancer core quality-of-life questionnaire and QLM-PR25 at weeks 0, 4, 12, and then every 12 weeks until progression. Scores from week 4 to 156 were analyzed with repeated measures modeling to calculate group means and differences. Deterioration-free survival was from random assignment until the earliest of death, clinical progression, discontinuation of study treatment, or a worsening of 10 points or more from baseline in fatigue, physical function, cognitive function, or overall health and quality of life (OHQL). HRQL scores range from 0 (lowest possible) to 100 (highest possible). HRQL was assessed in 1,042 of 1,125 participants (93%). Differences in means favored control over enzalutamide for fatigue (5.2, 95% CI, 3.6 to 6.9 P .001), cognitive function (4.0, 95% CI, 2.5 to 5.5 P .001), and physical function (2.6, 95% CI, 1.3 to 3.9 P .001), but not OHQL (1.2, 95% CI, −0.2 to 2.7 P = .1). Deterioration-free survival rates at 3 years, and log-rank P values comparing the whole distributions, favored enzalutamide over control for OHQL (31% v 17% P .0001), cognitive function (31% v 20% P = .001), and physical function (31% v 22% P .001), but not fatigue (24% v 18% P = .16). The effects of enzalutamide on HRQL were independent of baseline characteristics. Enzalutamide was associated with worsening of self-reported fatigue, cognitive function, and physical function, but not OHQL. Enzalutamide was associated with improved deterioration-free survival for OHQL, physical function, and cognitive function because delays in disease progression outweighed early deteriorations in these aspects of HRQL.
Publisher: MDPI AG
Date: 13-05-2020
DOI: 10.3390/IJMS21103452
Abstract: Awareness of the importance of immunity in controlling cancer development triggered research into the impact of its key oncogenic drivers on the immune response, as well as their value as targets for immunotherapy. At the heart of tumour suppression is p53, which was discovered in the context of viral infection and now emerges as a significant player in normal and cancer immunity. Wild-type p53 (wt p53) plays fundamental roles in cancer immunity and inflammation. Mutations in p53 not only cripple wt p53 immune functions but also sinisterly subvert the immune function through its neomorphic gain-of-functions (GOFs). The prevalence of mutant p53 across different types of human cancers, which are associated with inflammatory and immune dysfunction, further implicates mutant p53 in modulating cancer immunity, thereby promoting tumorigenesis, metastasis and invasion. In this review, we discuss several mutant p53 immune GOFs in the context of the established roles of wt p53 in regulating and responding to tumour-associated inflammation, and regulating innate and adaptive immunity. We discuss the capacity of mutant p53 to alter the tumour milieu to support immune dysfunction, modulate toll-like receptor (TLR) signalling pathways to disrupt innate immunity and subvert cell-mediated immunity in favour of immune privilege and survival. Furthermore, we expose the potential and challenges associated with mutant p53 as a cancer immunotherapy target and underscore existing therapies that may benefit from inquiry into cancer p53 status.
Publisher: Elsevier BV
Date: 2023
Publisher: MDPI AG
Date: 16-08-2022
Abstract: Metastatic prostate cancer is a lethal disease in patients incapable of responding to therapeutic interventions. Invasive prostate cancer spread is caused by failure of the normal anti-cancer defense systems that are controlled by the tumour suppressor protein, p53. Upon mutation, p53 malfunctions. Therapeutic strategies to directly re-empower the growth-restrictive capacities of p53 in cancers have largely been unsuccessful, frequently because of a failure to discriminate responses in diseased and healthy tissues. Our studies sought alternative prostate cancer drivers, intending to uncover new treatment targets. We discovered the oncogenic potency of MDM4 in prostate cancer cells, both in the presence and absence of p53 and also its mutation. We uncovered that sustained depletion of MDM4 is growth inhibitory in prostate cancer cells, involving either apoptosis or senescence, depending on the cell and genetic context. We identified that the potency of MDM4 targeting could be potentiated in prostate cancers with mutant p53 through the addition of a first-in-class small molecule drug that was selected as a p53 reactivator and has the capacity to elevate oxidative stress in cancer cells to drive their death.
Publisher: Wiley
Date: 31-08-2020
DOI: 10.1002/PROS.24056
Start Date: 2017
End Date: 2021
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2009
End Date: 2016
Funder: National Health and Medical Research Council
View Funded Activity