Sir Peter MacCallum Department of Oncology - Research Publications

Permanent URI for this collection

http://hdl.handle.net/11343/274

Filters

2019 - 2019 1 2020 - 2022 1
2
Reset filters

Settings
Statistics
Citations
Author: Gamell-Fulla, Cristina × Author: Keam, Simon × Start date: 2016 ×

Search Results

Now showing 1 - 2 of 2
  • Item
    Thumbnail Image
    Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status
    Mejia-Hernandez, JO ; Raghu, D ; Caramia, F ; Clemons, N ; Fujihara, K ; Riseborough, T ; Teunisse, A ; Jochemsen, AG ; Abrahmsen, L ; Blandino, G ; Russo, A ; Gamell, C ; Fox, SB ; Mitchell, C ; Takano, EA ; Byrne, D ; Miranda, PJ ; Saleh, R ; Thorne, H ; Sandhu, S ; Williams, SG ; Keam, SP ; Haupt, Y ; Haupt, S (MDPI, 2022-08)
    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.
  • Item
    Thumbnail Image
    E6AP Promotes a Metastatic Phenotype in Prostate Cancer
    Gamell, C ; Bandilovska, I ; Gulati, T ; Kogan, A ; Lim, SC ; Kovacevic, Z ; Takano, EA ; Timpone, C ; Agupitan, AD ; Litchfield, C ; Blandino, G ; Horvath, LG ; Fox, SB ; Williams, SG ; Russo, A ; Gallo, E ; Paul, PJ ; Mitchell, C ; Sandhu, S ; Keam, SP ; Haupt, S ; Richardson, DR ; Haupt, Y (CELL PRESS, 2019-12-20)
    Although primary prostate cancer is largely curable, progression to metastatic disease is associated with very poor prognosis. E6AP is an E3 ubiquitin ligase and a transcriptional co-factor involved in normal prostate development. E6AP drives prostate cancer when overexpressed. Our study exposed a role for E6AP in the promotion of metastatic phenotype in prostate cells. We revealed that elevated levels of E6AP in primary prostate cancer correlate with regional metastasis and demonstrated that E6AP promotes acquisition of mesenchymal features, migration potential, and ability for anchorage-independent growth. We identified the metastasis suppressor NDRG1 as a target of E6AP and showed it is key in E6AP induction of mesenchymal phenotype. We showed that treatment of prostate cancer cells with pharmacological agents upregulated NDRG1 expression suppressed E6AP-induced cell migration. We propose that the E6AP-NDRG1 axis is an attractive therapeutic target for the treatment of E6AP-driven metastatic prostate cancer.