A5083066252- Prostate Cancer Treatment and Research
- Advanced Breast Cancer Therapies
- Cancer, Lipids, and Metabolism
- Cancer-related Molecular Pathways
- PARP inhibition in cancer therapy
- Histone Deacetylase Inhibitors Research
- Cancer-related molecular mechanisms research
- Epigenetics and DNA Methylation
- Estrogen and related hormone effects
- RNA modifications and cancer
- Ubiquitin and proteasome pathways
- Metabolism, Diabetes, and Cancer
- Ferroptosis and cancer prognosis
- NF-κB Signaling Pathways
- Cytokine Signaling Pathways and Interactions
- DNA Repair Mechanisms
- Cancer-related gene regulation
- RNA Research and Splicing
- Sesquiterpenes and Asteraceae Studies
- Cancer, Hypoxia, and Metabolism
- Inflammatory mediators and NSAID effects
- Effects of Radiation Exposure
- interferon and immune responses
- Chemical Reactions and Isotopes
- Pharmacological Effects and Toxicity Studies
Centre for Cancer Biology
2022-2024
The University of Adelaide
2022-2024
Dana-Farber Cancer Institute
2019-2021
Harvard University
2019-2021
Flinders Medical Centre
2013-2019
Flinders University
2014-2019
Abstract The increased treatment of metastatic castration-resistant prostate cancer (mCRPC) with second-generation antiandrogen therapies (ADT) has coincided a greater incidence lethal, aggressive variant (AVPC) tumors that have lost dependence on androgen receptor (AR) signaling. These AR-independent may also transdifferentiate to express neuroendocrine lineage markers and are termed (NEPC). Recent evidence suggests kinase signaling be an important driver NEPC. To identify targetable...
Radiotherapy is widely used in cancer treatment, however the benefits can be limited by radiation-induced damage to neighboring normal tissues. Parthenolide (PTL) exhibits anti-inflammatory and anti-tumor properties selectively induces radiosensitivity prostate cell lines, while protecting primary epithelial lines from damage. Low doses of radiation have also been shown protect subsequent high-dose-radiation-induced apoptosis as well DNA These PTL low-dose could improve radiotherapy killing...
We investigated the potential of combining hypoglycemic drug metformin (MET) and antiepileptic valproic acid (VPA), which act via different biochemical pathways, to provide enhanced antitumor responses in prostate cancer. Prostate cancer cell lines (LNCaP PC-3), normal epithelial cells (PrEC), patient-derived tumor explants were treated with MET and/or VPA. Proliferation apoptosis assessed. The role p53 response + VPA was assessed using RNAi LNCaP (p53+) ectopic expression PC-3 (p53-)....
Phenotypic plasticity is a recognized mechanism driving therapeutic resistance in patients with prostate cancer. Although underlying molecular causations phenotypic have been identified, success yet to be achieved. To identify putative master regulator transcription factors (MR-TF) cancer, this work utilized multiomic approach using genetically engineered mouse models of cancer combined patient data MYB proto-oncogene like 2 (MYBL2) as significantly enriched factor exhibiting plasticity....
The effects of ionizing radiation on DNA methylation are importance due to the role that plays in maintaining genome stability, and presence aberrant many cancers. There is limited evidence radiation-sensitivity may influence modulation by radiation, resulting a loss methylation. BALB/c, CBA C57Bl/6 strains most commonly utilized mouse research classified as sensitive (BALB/c CBA) or resistant (C57Bl/6). We present here first direct comparison changes repeat element (L1, B1 Intracisternal A...
Abstract NF-κB activation has been linked to prostate cancer progression and is commonly observed in castrate-resistant disease. It suggested that NF-κB–driven resistance androgen-deprivation therapy (ADT) cells may be mediated by aberrant androgen receptor (AR) AR splice variant production. Preventing ADT therefore achieved using inhibitors. However, low oral bioavailability high toxicity of inhibitors a major challenge for clinical translation. Dimethylaminoparthenolide (DMAPT) an...
Phenotypic plasticity is a recognized mechanism driving therapeutic resistance in prostate cancer (PCa) patients. While underlying molecular causations phenotypic have been identified, success yet to be achieved. To identify putative master regulator transcription factors (MR-TF) PCa, this work utilized multiomic approach using genetically engineered mouse models of combined with patient data MYBL2 as significantly enriched factor PCa exhibiting plasticity. Genetic inhibition
The low dose radioadaptive response has been shown to be protective against high doses of radiation as well aging-induced genomic instability. We hypothesised that a single whole-body exposure would induce thereby reducing or abrogating aging-related changes in repeat element DNA methylation mice. Following sham 10 mGy X-irradiation, serial peripheral blood sampling was performed and differences Long Interspersed Nucleic Element 1 (L1), B1 Intracisternal-A-Particle (IAP) between samples were...
The hypoglycemic drug metformin (MET) and the anti-epileptic valproic acid (VPA) have individually shown anti-tumor effects in prostate cancer vitro. present study intended to investigate efficacy of combination MET VPA treatment a pre-clinical xenograft model.Prostate cell lines (LNCaP PC-3) were inoculated under skin BALB/c nude mice. mice treated with 200 μl/ml and/or 0.4% (w/v) diluted drinking water, or vehicle control, monitored until tumor volume reached 2,000 mm3 Evaluation toxicity...
While radiotherapy is widely used in cancer treatment, the benefits can be limited by radiation-induced damage to neighboring healthy tissues. We previously demonstrated mice that anti-inflammatory compound dimethylaminoparthenolide (DMAPT) selectively induces radiosensitivity prostate tumor tissue from transgenic adenocarcinoma of mouse (TRAMP) mice, while simultaneously protecting tissues 6 Gy whole-body apoptosis. Here, we examined radioprotective effect DMAPT on fibrosis normal after a...
Abstract Prostate cancers are considered immunologically ‘cold’ tumors given the very few patients who respond to checkpoint inhibitor therapy (CPI). Recently, enrichment of interferon (IFN) response genes predicts a favorable CPI across various disease sites. The enhancer zeste homolog-2 (EZH2) is over-expressed in prostate cancer and known negatively regulate IFN genes. Here, we demonstrate that inhibition EZH2 catalytic activity models derepresses expression double-strand RNA (dsRNA),...
Abstract Increased treatment of metastatic castration resistant prostate cancer (mCRPC) with second-generation anti-androgen therapies (ADT) has coincided a greater incidence lethal, aggressive variant (AVPC) tumors that have lost androgen receptor (AR) signaling. AVPC may also express neuroendocrine markers, termed (NEPC). Recent evidence suggests kinase signaling be an important driver NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing AR-negative...
Chemoprevention trials for prostate cancer by androgen receptor or synthesis inhibition have proven ineffective. Recently, it has been demonstrated that the histone methlytransferase, EZH2 is deregulated in mouse and human high-grade prostatic intraepithelial neoplasia (HG-PIN). Using preclinical models of cancer, we demonstrate genetic chemical disruption expression catalytic activity reversed HG-PIN phenotype. Furthermore, function was associated with loss cellular proliferation induction...
<p>Increased Mybl2 expression supports stem-related gene signatures in murine and human prostate cancer. <b>A,</b> Two-dimensional principal component analysis visualization of bulk RNA-seq performed DKO Ctl vs. <i>Mybl2</i> KO cells (left) PPKO cells. <b>B,</b> Venn diagram representation down- upregulated genes from the DEG between showed that both cell lines shared 197 down 127 genes. The <i>P</i> adjusted value used to calculate was...
<p>Mybl2 is a genetic dependency associated with CDK2 expression in NEPC. <b>A,</b> Tumoral growth curve of murine DKO Ctl and <i>Mybl2</i> KO cells (<b>B</b>) PPKO Mybl2 NOD SCID mice. Tumor was monitored by serial caliper measurements every second day for 16 days (D16). weight measured at D16 after dissection (<i>n</i> = 5 mice per treatment group (±1 SEM). <b>C,</b> Top responses from the cancer therapeutics response portal...
<p>Combined genes enriched in human NEPC, PDX samples and NE-like mouse models</p>
<p>Summary of Peak calls following H3K27ac ChIPseq with Atacseq integration.</p>
<p>Supplement Figure 2. A. SKO, DKO, and PPKO were cultured as 3-dimensional spheroids treated with the indicated concentrations of CDK2 inhibitor - BGG463 over 72 hours. Cell growth was determined by CellTiter-Glo luminescent cell viability assay. B. Western blot analysis for Cdk2, Cdk5, Vinculin following DKO concentration PROTAC CPS2. Full western membranes C) CDK2, D) CDK5, E) vinculin.</p>
<p>A. Full membrane following CRISPR targeting of Mybl2 indicating specific our target gene. B. DKO-Ctl and DKO-Mybl2 KO cells were cultured as 2-dimensional monolayers overall cell growth was determined by CellTiter-Glo luminescent viability assay.</p>
<p>A. Full membrane following CRISPR targeting of Mybl2 indicating specific our target gene. B. DKO-Ctl and DKO-Mybl2 KO cells were cultured as 2-dimensional monolayers overall cell growth was determined by CellTiter-Glo luminescent viability assay.</p>
<p>Mybl2 is a genetic dependency associated with CDK2 expression in NEPC. <b>A,</b> Tumoral growth curve of murine DKO Ctl and <i>Mybl2</i> KO cells (<b>B</b>) PPKO Mybl2 NOD SCID mice. Tumor was monitored by serial caliper measurements every second day for 16 days (D16). weight measured at D16 after dissection (<i>n</i> = 5 mice per treatment group (±1 SEM). <b>C,</b> Top responses from the cancer therapeutics response portal...
<p>Mybl2 supports tumoral proliferation and promotes self-renewal in prostate cancer cell line models. <b>A,</b> Normalized gene expression of <i>MYBL2</i> human lines. DEMETER dependency MYB family members across lines indicating as a significant compared with other members. <b>B,</b> Schematic representation the DKO Ctl <i>Mybl2</i> KO PPKO generation using two-step CRISPR/Cas9 method. Western blot Mybl2 protein levels Ctl, KO,...