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Smith M.A.,U.S. National Cancer Institute | Reynolds C.P.,Texas Tech University Health Sciences Center | Kang M.H.,Texas Tech University Health Sciences Center | Kolb E.A.,DuPont Company | And 9 more authors.
Clinical Cancer Research | Year: 2015

Purpose: Inhibitors of PARP, an enzyme involved in base excision repair, have demonstrated single-agent activity against tumors deficient in homologous repair processes. Ewing sarcoma cells are also sensitive to PARP inhibitors, although the mechanism is not understood. Here, we evaluated the stereoselective PARP inhibitor, talazoparib (BMN 673), combined with temozolomide or topotecan. Experimental Design: Talazoparib was tested in vitro in combination with temozolomide (0.3-1,000 μmol/L) or topotecan (0.03-100 nmol/L) and in vivo at a dose of 0.1 mg/kg administered twice daily for 5 days combined with temozolomide (30 mg/kg/daily × 5; combination A) or 0.25 mg/kg administered twice daily for 5 days combined with temozolomide (12 mg/kg/daily × 5; combination B). Pharmacodynamic studies were undertaken after 1 or 5 days of treatment. Results: In vitro talazoparib potentiated the toxicity of temo-zolomide up to 85-fold, with marked potentiation in Ewing sarcoma and leukemia lines (30-50-fold). There was less potentiation for topotecan. In vivo, talazoparib potentiated the toxicity of temozolomide, and combination A and combination B represent the MTDs when combined with low-dose or high-dose talazoparib, respectively. Both combinations demonstrated significant synergism against 5 of 10 Ewing sarcoma xenografts. The combination demonstrated modest activity against most other xenograft models. Pharmacodynamic studies showed a treatment-induced complete loss of PARP only in tumor models sensitive to either talazoparib alone or talazoparib plus temozolomide. Conclusions: The high level of activity observed for talazoparib plus temozolomide in Ewing sarcoma xenografts makes this an interesting combination to consider for pediatric evaluation. © 2014 American Association for Cancer Research.


Po'Uha S.T.,Childrens Cancer Institute Australia for Medical Research | Po'Uha S.T.,University of New South Wales | Shum M.S.Y.,Childrens Cancer Institute Australia for Medical Research | Shum M.S.Y.,University of New South Wales | And 4 more authors.
Oncogene | Year: 2010

LIM-kinase 2 (LIMK2) belongs to the LIMK family of proteins, which comprises LIMK1 and LIMK2. Both proteins regulate actin polymerization through phosphorylation and inactivation of the actin depolymerizing factor cofilin. In this study, we show that the level of LIMK2 protein is increased in neuroblastoma, BE(2)-C cells, selected for resistance to microtubule- destabilizing agents, vincristine and colchicine. However, the level of phosphorylated LIMK1 and LIMK2 was similar in the resistant and parental BE(2)-C cells. In contrast, the level of phospho-cofilin was greatly increased in the drug-resistant cells. Downregulation of LIMK2 expression increases sensitivity of neuroblastoma SH-EP cells to vincristine and vinblastine but not to microtubule-stabilizing agents, while it's overexpression increased its resistance to vincristine. Its vincristine-induced mitotic arrest was moderately inhibited in the LIMK2 knockdown cells, suggesting that the increased drug sensitivity is through an alternative mechanism other then mitotic arrest and apoptosis. Moreover, downregulation of LIMK2 expression induces formation of abnormal mitotic spindles, an effect enhanced in the presence of microtubule-destabilizing agents. LIMK2 is important for normal mitotic spindle formation and altered LIMK2 expression mediates sensitivity to microtubule destabilizing agents. These findings suggest that inhibition of LIMK2 activity may be used for the treatment of tumors resistant to microtubule-destabilizing drugs. © 2010 Macmillan Publishers Limited All rights reserved.


Song R.,University of Technology, Sydney | Liu Q.,University of Technology, Sydney | Liu T.,Childrens Cancer Institute Australia for Medical Research | Li J.,University of Technology, Sydney
BMC Genomics | Year: 2015

Background: Intensive research based on the inverse expression relationship has been undertaken to discover the miRNA-mRNA regulatory modules involved in the infection of Hepatitis C virus (HCV), the leading cause of chronic liver diseases. However, biological studies in other fields have found that inverse expression relationship is not the only regulatory relationship between miRNAs and their targets, and some miRNAs can positively regulate a mRNA by binding at the 5' UTR of the mRNA.Results: This work focuses on the detection of both inverse and positive regulatory relationships from a paired miRNA and mRNA expression data set of HCV patients through a 'change-to-change' method which can derive connected discriminatory rules. Our study uncovered many novel miRNA-mRNA regulatory modules. In particular, it was revealed that GFRA2 is positively regulated by miR-557, miR-765 and miR-17-3p that probably bind at different locations of the 5' UTR of this mRNA. The expression relationship between GFRA2 and any of these three miRNAs has not been studied before, although separate research for this gene and these miRNAs have all drawn conclusions linked to hepatocellular carcinoma. This suggests that the binding of mRNA GFRA2 with miR-557, miR-765, or miR-17-3p, or their combinations, is worthy of further investigation by experimentation. We also report another mRNA QKI which has a strong inverse expression relationship with miR-129 and miR-493-3p which may bind at the 3' UTR of QKI with a perfect sequence match. Furthermore, the interaction between hsa-miR-129-5p (previous ID: hsa-miR-129) and QKI is supported with CLIP-Seq data from starBase. Our method can be easily extended for the expression data analysis of other diseases.Conclusion: Our rule discovery method is useful for integrating binding information and expression profile for identifying HCV miRNA-mRNA regulatory modules and can be applied to the study of the expression profiles of other complex human diseases. © 2015 Song et al.; licensee BioMed Central Ltd.


Wilson C.L.,Childrens Cancer Institute Australia for Medical Research | Cohn R.J.,Sydney Childrens Hospital | Johnston K.A.,Sydney Childrens Hospital | Ashton L.J.,Childrens Cancer Institute Australia for Medical Research
Medical Journal of Australia | Year: 2010

Objective: The aim of this study was to characterise rates of late mortality and second cancers in an Australian cohort of childhood cancer survivors and compare these to rates observed in the New South Wales population. Design, setting and participants: Records for 896 childhood cancer survivors treated at the Sydney Children's Hospital between 1972 and 1999 were linked to the National Death Index and NSW Central Cancer Registry to identify deaths and notifications of second cancers. Survivors were defined as those alive for at least 5 years after diagnosis and were followed until death or 31 December 2004, whichever occurred first. Main outcome measures: Standardised mortality ratios (SMRs) and standardised incidence ratios (SIRs) were used as measures of relative risk. A Cox proportional hazard model was used to quantify the influence of demographic and disease-related characteristics on the risk of death and second cancers. Results: The SMR and SIR were 7.46 and 4.98 times higher, respectively, among cancer survivors relative to the NSW population. Relative mortality was highest in survivors of soft-tissue sarcoma (SMR, 18.95 [95% CI, 6.88-40.81]) and central nervous system (CNS) malignancies (SMR, 16.78 [95% CI, 7.62-31.64]). The leading causes of death included recurrence of the primary childhood cancer (55%) and second cancers (12%), as well as treatment-related complications (17%) The most frequently observed second cancers were bone and thyroid cancers, melanoma, and CNS malignancies, and second cancers were most common among survivors of leukaemia, soft-tissue sarcoma and Hodgkin's lymphoma. Conclusions: Compared with the general population, survivors of childhood cancer in Australia are at increased risk of late mortality and second cancers. These findings highlight a continuing need to assess health issues faced by childhood cancer survivors and develop strategies to minimise the adverse outcomes associated with treatment for childhood cancer.


Lynch G.W.,University of Sydney | Selleck P.,CSIRO | Church W.B.,University of Sydney | Sullivan J.S.,University of Sydney | Sullivan J.S.,Childrens Cancer Institute Australia for Medical Research
Immunology and Cell Biology | Year: 2012

Fundamentally new approaches are required for the development of vaccines to pre-empt and protect against emerging and pandemic influenzas. Current strategies involve post-emergent homotypic vaccines that are modelled upon select circulating seasonal influenzas, but cannot induce cross-strain protection against newly evolved or zoonotically introduced highly pathogenic influenza (HPI). Avian H5N1 and the less-lethal 2009 H1N1 and their reassortants loom as candidates to seed a future HPI pandemic. Therefore, more universal seasoned vaccine approaches are urgently needed for heterotypic protection ahead of time. Pivotal to this is the need to understand mechanisms that can deliver broad strain protection. Heterotypic and heterosubtypic humoral immunities have largely been overlooked for influenza cross-protection, with most seasoned vaccine efforts for humans focussed on heterotypic cellular immunity. However, 5 years ago we began to identify direct and indirect indicators of humoral-herd immunity to protein sites preserved among H1N1, H3N2 and H5N1 influenzas. Since then the evidence for cross-protective antibodies in humans has been accumulating. Now proposed is a rationale to stimulate and enhance pre-existing heterotypic humoral responses that, together with cell-mediated initiatives, will deliver pre-emptive and universal human protection against emerging epidemic and pandemic influenzas. © 2012 Australasian Society for Immunology Inc. All rights reserved.


McCarroll J.,University of Massachusetts Medical School | McCarroll J.,Childrens Cancer Institute Australia for Medical Research | Baigude H.,University of Massachusetts Medical School | Baigude H.,Burnham Institute for Medical Research | And 4 more authors.
Bioconjugate Chemistry | Year: 2010

Single-walled carbon nanotubes (SWNT) have unique electronic, mechanical, and structural properties as well as chemical stability that make them ideal nanomaterials for applications in materials science and medicine. Here, we report the design and creation of a novel strategy for functionalizing SWNT to systemically silence a target gene in mice by delivering siRNA at doses of <1 mg/kg. SWNT were functionalized with lipids and natural amino acid-based dendrimers (TOT) and complexed to siRNA. Our model study of the silencing efficiency of the TOT-siRNA complex showed that, in mice injected at 0.96 mg/kg, an endogenous gene for apoliproprotein B (ApoB) was silenced in liver, plasma levels of ApoB decreased, and total plasma cholesterol decreased. TOT-siRNA treatment was nontoxic and did not induce an immune response. Most (80%) of the RNA trigger molecules assembled with TOT were cleared from the body 48 h after injection, suggesting that the nanotubes did not cause siRNA aggregation or inhibit biodegradation and drug clearance in vivo. These results provide the first evidence that nanotubes can be functionalized with lipids and amino acids to systemically deliver siRNA. This new technology not only can be used for systemic RNAi, but may also be used to deliver other drugs in vivo. © 2010 American Chemical Society.


McDonald W.J.,Dalhousie University | Sangster S.M.,Dalhousie University | Moffat L.D.,Dalhousie University | Henderson M.J.,Childrens Cancer Institute Australia for Medical Research | Too C.K.L.,Dalhousie University
Journal of Cellular Biochemistry | Year: 2010

Mammalian α4 phosphoprotein, the homolog of yeast Tap42, is a component of the mammalian target-of-rapamycin (mTOR) pathway that regulates ribogenesis, the initiation of translation, and cell-cycle progression. α4 is known to interact with the catalytic subunit of protein phosphatase 2A (PP2Ac) and to regulate PP2A activity. Using α4 as bait in yeast two-hybrid screening of a human K562 erythroleukemia cDNA library, EDD (E3 isolated by differential display) E3 ubiquitin ligase was identified as a new protein partner of α4. EDD is the mammalian ortholog of Drosophila hyperplastic discs gene (hyd) that controls cell proliferation during development. The EDD protein contains a PABC domain that is present in poly(A)-binding protein (PABP), suggesting that PABP may also interact with α4. PABP recruits translation factors to the poly(A)-tails of mRNAs. In the present study, immunoprecipitation/immunoblotting (IP/IB) analyses showed a physical interaction between α4 and EDD in rat Nb2 T-lymphoma and human MCF-7 breast cancer cell lines. α4 also interacted with PABP in Nb2, MCF-7 and the human Jurkat T-leukemic and K562 myeloma cell lines. COS-1 cells, transfected with Flag-tagged-pSG5-EDD, gave a (Flag)-EDD-α4 immunocomplex. Furthermore, deletion mutants of α4 were constructed to determine the binding site for EDD. IP/IB analysis showed that EDD bound to the C-terminal region of α4, independent of the α4-PP2Ac binding site. Therefore, in addition to PP2Ac, α4 interacts with EDD and PABP, suggesting its involvement in multiple steps in the mTOR pathway that leads to translation initiation and cell-cycle progression. © 2010 Wiley-Liss, Inc.


Shahbazi J.,Childrens Cancer Institute Australia for Medical Research | Shahbazi J.,University of New South Wales | Lock R.,Childrens Cancer Institute Australia for Medical Research | Liu T.,Childrens Cancer Institute Australia for Medical Research | Liu T.,University of New South Wales
Frontiers in Genetics | Year: 2013

Tumor protein 53-induced nuclear protein 1 (TP53INP1) is a stress-induced p53-target gene whose expression is modulated by transcription factors such as p53, p73, and E2F1. TP53INP1 gene encodes two isoforms of TP53INP1 proteins, TP53INP1α and TP53INP1β, both of which appear to be key elements in p53 function. In association with homeodomain-interacting protein kinase-2 (HIPK2), TP53INP1 phosphorylates p53 protein at Serine-46. This enhances p53 protein stability and its transcriptional activity, leading to transcriptional activation of p53-target genes such as p21 and PIG3, cell growth arrest and apoptosis upon DNA damage stress. The anti-proliferative and pro-apoptotic activities of TP53INP1 indicate that TP53INP1has an important role in cellular homeostasis and DNA damage response. Deficiency in TP53INP1 expression results in increased tumorigenesis, whereas TP53INP1 expression is repressed during early stages of cancer by factors such as miR-155. This review aims to summarize the roles of TP53INP1 in blocking tumor progression through p53-dependant and p53-independent pathways, as well as the elements which repress TP53INP1 expression, hencehighlighting its potential as a therapeutic target in cancer treatment. © 2013 Shahbazi, Lock and Liu.


Wong L.,University of New South Wales | Kavallaris M.,Childrens Cancer Institute Australia for Medical Research | Bulmus V.,University of New South Wales
Polymer Chemistry | Year: 2011

Doxorubicin (Dox)-conjugated, poly(ethylene glycol) (PEG) shielded, reversibly crosslinked particles were prepared by a one-pot thiol-ene reaction from a RAFT-synthesized well-defined homopolymer scaffold, poly(pyridyldisulfide ethylmethacrylate) (PPDSM). Dox and PEG modified with maleimide end-groups (mal-Dox and mal-PEG), were covalently attached in one pot to free thiol groups of PPDSM (M n = 8900 g mol -1 and PDI = 1.18) in the presence of a disulfide reducing agent. ∼ 50% of the total pyridyldisulfide units were conjugated with Dox and PEG (with an equal mol ratio). Particles with an average hydrodynamic diameter of 192 ± 28 nm were observed to form after conjugation. Incubation of these particles with a disulfide reducing agent resulted in the disassociation of the particles. The release of Dox from the particles was pH dependent. The Dox-conjugated PEGylated particles (with a Dox content of 8 wt%) inhibited the viability of human cervical carcinoma cells (HeLa) with an IC 50 value of 8 × 10 -7 M, determined by an Alamar Blue assay, while the IC 50 of free Dox was 1 × 10 -7 M. The fluorescence microscopy analyses of the HeLa cells after incubation with the particles for varying times showed that the Dox carried by the particles is taken up efficiently by the cells. © 2011 The Royal Society of Chemistry.


Patent
INC Research, Panacela Labs and Childrens Cancer Institute Australia For Medical Research | Date: 2013-10-14

Pharmaceutical compositions including a Myc inhibitor are provided. Also provided are methods for treating cancer including administration of compounds that inhibit oncoprotein Myc.

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