Sir Peter MacCallum Department of Oncology - Research Publications
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ItemEstrogen Receptor beta Activation Impairs Prostatic Regeneration by Inducing Apoptosis in Murine and Human Stem/Progenitor Enriched Cell Populations(PUBLIC LIBRARY SCIENCE, 2012-07-10)Androgen depletion is the primary treatment for prostate disease; however, it fails to target residual castrate-resistant cells that are regenerative and cells of origin of prostate cancer. Estrogens, like androgens, regulate survival in prostatic cells, and the goal of this study was to determine the advantages of selective activation of estrogen receptor β (ERβ) to induce cell death in stem cells that are castrate-resistant. Here we show two cycles of short-term ERβ agonist (8β-VE2) administration this treatment impairs regeneration, causing cystic atrophy that correlates with sustained depletion of p63+ basal cells. Furthermore, agonist treatment attenuates clonogenicity and self-renewal of murine prostatic stem/progenitor cells and depletes both murine (Lin(-)Sca1(+)CD49f(hi)) and human (CD49f(hi)Trop2(hi)) prostatic basal cells. Finally, we demonstrate the combined added benefits of selective stimulation of ERβ, including the induction of cell death in quiescent post-castration tissues. Subsequent to castration ERβ-induces further apoptosis in basal, luminal and intermediate cells. Our results reveal a novel benefit of ERβ activation for prostate disease and suggest that combining selective activation of ERβ with androgen-deprivation may be a feasible strategy to target stem cells implicated in the origin of prostatic disease.
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ItemTargeting mTOR-dependent with specific inhibitors: a model for personalized medicine based on molecular diagnoses(MULTIMED INC, 2009-02-01)Cancer cells are characterized by aberrant growth arising from deregulated signalling pathways. The mammalian target of rapamycin (mTOR) pathway integrates multiple growth signals coming from both intracellular and extracellular cues. In this short review, we summarize what is known about the efficacy of targeting the mTOR pathway to treat cancer patients, and we explain the rationale behind promising new inhibitors that could show more potent tumour growth inhibition than did the first generation of these drugs.
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ItemPiloting the role of a pharmacist in a community palliative care multidisciplinary team: an Australian experience.(Springer Science and Business Media LLC, 2011-10-31)BACKGROUND: While the home is the most common setting for the provision of palliative care in Australia, a common problem encountered here is the inability of patient/carers to manage medications, which can lead to misadventure and hospitalisation. This can be averted through detection and resolution of drug related problems (DRPs) by a pharmacist; however, they are rarely included as members of the palliative care team. The aim of this study was to pilot a model of care that supports the role of a pharmacist in a community palliative care team. A component of the study was to develop a cost-effective model for continuing the inclusion of a pharmacist within a community palliative care service. METHODS: The study was undertaken (February March 2009-June 2010) in three phases. Development (Phase 1) involved a literature review; scoping the pharmacist's role; creating tools for recording DRPs and interventions, a communication and education strategy, a care pathway and evidence based patient information. These were then implemented in Phase 2. Evaluation (Phase 3) of the impact of the pharmacist's role from the perspectives of team members was undertaken using an online survey and focus group. Impact on clinical outcomes was determined by the number of patients screened to assess their risk of medication misadventure, as well as the number of medication reviews and interventions performed to resolve DRPs. RESULTS: The pharmacist screened most patients (88.4%, 373/422) referred to the palliative care service to assess their risk of medication misadventure, and undertook 52 home visits. Medication reviews were commonly conducted at the majority of home visits (88%, 46/52), and a variety of DRPs (113) were detected at this point, the most common being "patient requests drug information" (25%, 28/113) and "condition not adequately treated" (22%, 25/113). The pharmacist made 120 recommendations in relation to her interventions.Fifty percent of online survey respondents (10/20) had interacted 10 or more times with the pharmacist for advice. All felt that the pharmacist's role was helpful, improving their knowledge of the different medications used in palliative care. The six team members who participated in the focus group indicated that there were several benefits of the pharmacist's contributions towards medication screening and review. CONCLUSIONS: The inclusion of a pharmacist in a community palliative care team lead to an increase in the medication-related knowledge and skills of its members, improved patients' medication management, and minimised related errors. The model of care created can potentially be duplicated by other palliative care services, although its cost-effectiveness was unable to be accurately tested within the study.
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ItemKnowledge, attitudes and practices of health professionals and women towards medication use in breastfeeding: A review.(Springer Science and Business Media LLC, 2011-08-26)Many breastfeeding women require and regularly take medicines, especially those available over-the-counter, and the safe use of these is dependent on the advice provided by health professionals such as general practitioners and pharmacists. The primary aim of this review therefore, was to investigate the literature relating to health professionals' and women's knowledge, attitudes and practices towards medication use and safety in breastfeeding. The limited literature that was uncovered identified that general practitioners and pharmacists have poor knowledge, but positive attitudes, and variable practices that are mostly guided by personal experience. They tend to make decisions about the use of a medicine whilst breastfeeding based on the potential 'risk' that it poses to the infant in terms of possible adverse reactions, rather than its 'compatibility' with breast milk. The decision-making process between health professionals and women is usually not a negotiated process, and women are often asked to stop breastfeeding whilst taking a medicine. Women, in turn, are left dissatisfied with the advice received, many choosing not to initiate therapy or not to continue breastfeeding. Some directions for future research have been suggested to address the issues identified in this critical area. This review is important from a societal perspective because many breastfeeding women require and regularly take medications, especially those available without prescription, and the safe use of these is dependent on the advice provided by health professionals, which is ultimately influenced by their knowledge, attitudes and practices. However, there is an absence of high quality evidence from randomised controlled trials on the safety of medications taken during breastfeeding, which naturally would hinder health professionals from appropriately advising women. It is equally important to know about women's experiences of advice received from health professionals, and whether there is consistency between recommendations made across resources on medication safety in breastfeeding, in order to gain a full understanding of the issues prevalent in this area of practice.
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ItemDifferential expression of selected histone modifier genes in human solid cancers(BMC, 2006-04-25)BACKGROUND: Post-translational modification of histones resulting in chromatin remodelling plays a key role in the regulation of gene expression. Here we report characteristic patterns of expression of 12 members of 3 classes of chromatin modifier genes in 6 different cancer types: histone acetyltransferases (HATs)- EP300, CREBBP, and PCAF; histone deacetylases (HDACs)- HDAC1, HDAC2, HDAC4, HDAC5, HDAC7A, and SIRT1; and histone methyltransferases (HMTs)- SUV39H1and SUV39H2. Expression of each gene in 225 samples (135 primary tumours, 47 cancer cell lines, and 43 normal tissues) was analysedby QRT-PCR, normalized with 8 housekeeping genes, and given as a ratio by comparison with a universal reference RNA. RESULTS: This involved a total of 13,000 PCR assays allowing for rigorous analysis by fitting a linear regression model to the data. Mutation analysis of HDAC1, HDAC2, SUV39H1, and SUV39H2 revealed only two out of 181 cancer samples (both cell lines) with significant coding-sequence alterations. Supervised analysis and Independent Component Analysis showed that expression of many of these genes was able to discriminate tumour samples from their normal counterparts. Clustering based on the normalized expression ratios of the 12 genes also showed that most samples were grouped according to tissue type. Using a linear discriminant classifier and internal cross-validation revealed that with as few as 5 of the 12 genes, SIRT1, CREBBP, HDAC7A, HDAC5 and PCAF, most samples were correctly assigned. CONCLUSION: The expression patterns of HATs, HDACs, and HMTs suggest these genes are important in neoplastic transformation and have characteristic patterns of expression depending on tissue of origin, with implications for potential clinical application.
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ItemCbl associates with Pyk2 and Src to regulate Src kinase activity, alpha(v)beta(3) integrin-mediated signaling, cell adhesion, and osteoclast motility(ROCKEFELLER UNIV PRESS, 2001-01-08)The signaling events downstream of integrins that regulate cell attachment and motility are only partially understood. Using osteoclasts and transfected 293 cells, we find that a molecular complex comprising Src, Pyk2, and Cbl functions to regulate cell adhesion and motility. The activation of integrin alpha(v)beta(3) induces the [Ca(2+)](i)-dependent phosphorylation of Pyk2 Y402, its association with Src SH2, Src activation, and the Src SH3-dependent recruitment and phosphorylation of c-Cbl. Furthermore, the PTB domain of Cbl is shown to bind to phosphorylated Tyr-416 in the activation loop of Src, the autophosphorylation site of Src, inhibiting Src kinase activity and integrin-mediated adhesion. Finally, we show that deletion of c Src or c-Cbl leads to a decrease in osteoclast migration. Thus, binding of alpha(v)beta(3) integrin induces the formation of a Pyk2/Src/Cbl complex in which Cbl is a key regulator of Src kinase activity and of cell adhesion and migration. These findings may explain the osteopetrotic phenotype in the Src(-/-) mice.
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ItemA mouse with a loss-of-function mutation in the c-Cbl TKB domain shows perturbed thymocyte signaling without enhancing the activity of the ZAP-70 tyrosine kinase(ROCKEFELLER UNIV PRESS, 2003-02-17)The unique tyrosine kinase binding (TKB) domain of Cbl targets phosphorylated tyrosines on activated protein tyrosine kinases (PTKs); this targeting is considered essential for Cbl proteins to negatively regulate PTKs. Here, a loss-of-function mutation (G304E) in the c-Cbl TKB domain, first identified in Caenorhabditis elegans, was introduced into a mouse and its effects in thymocytes and T cells were studied. In marked contrast to the c-Cbl knockout mouse, we found no evidence of enhanced activity of the ZAP-70 PTK in thymocytes from the TKB domain mutant mouse. This finding contradicts the accepted mechanism of c-Cbl-mediated negative regulation, which requires TKB domain targeting of phosphotyrosine 292 in ZAP-70. However, the TKB domain mutant mouse does show aspects of enhanced signaling that parallel those of the c-Cbl knockout mouse, but these involve the constitutive activation of Rac and not enhanced PTK activity. Furthermore, the enhanced signaling in CD4(+)CD8(+) double positive thymocytes appears to be compensated by the selective down-regulation of CD3 on mature thymocytes and peripheral T cells from both strains of mutant c-Cbl mice.
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ItemExploiting the noise: improving biomarkers with ensembles of data analysis methodologies(BMC, 2012-11-12)BACKGROUND: The advent of personalized medicine requires robust, reproducible biomarkers that indicate which treatment will maximize therapeutic benefit while minimizing side effects and costs. Numerous molecular signatures have been developed over the past decade to fill this need, but their validation and up-take into clinical settings has been poor. Here, we investigate the technical reasons underlying reported failures in biomarker validation for non-small cell lung cancer (NSCLC). METHODS: We evaluated two published prognostic multi-gene biomarkers for NSCLC in an independent 442-patient dataset. We then systematically assessed how technical factors influenced validation success. RESULTS: Both biomarkers validated successfully (biomarker #1: hazard ratio (HR) 1.63, 95% confidence interval (CI) 1.21 to 2.19, P = 0.001; biomarker #2: HR 1.42, 95% CI 1.03 to 1.96, P = 0.030). Further, despite being underpowered for stage-specific analyses, both biomarkers successfully stratified stage II patients and biomarker #1 also stratified stage IB patients. We then systematically evaluated reasons for reported validation failures and find they can be directly attributed to technical challenges in data analysis. By examining 24 separate pre-processing techniques we show that minor alterations in pre-processing can change a successful prognostic biomarker (HR 1.85, 95% CI 1.37 to 2.50, P < 0.001) into one indistinguishable from random chance (HR 1.15, 95% CI 0.86 to 1.54, P = 0.348). Finally, we develop a new method, based on ensembles of analysis methodologies, to exploit this technical variability to improve biomarker robustness and to provide an independent confidence metric. CONCLUSIONS: Biomarkers comprise a fundamental component of personalized medicine. We first validated two NSCLC prognostic biomarkers in an independent patient cohort. Power analyses demonstrate that even this large, 442-patient cohort is under-powered for stage-specific analyses. We then use these results to discover an unexpected sensitivity of validation to subtle data analysis decisions. Finally, we develop a novel algorithmic approach to exploit this sensitivity to improve biomarker robustness.
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ItemKoilocytes indicate a role for human papilloma virus in breast cancer.(Springer Science and Business Media LLC, 2009-10-20)BACKGROUND: High-risk human papilloma viruses (HPVs) are candidates as causal viruses in breast cancer. The scientific challenge is to determine whether HPVs are causal and not merely passengers or parasites. Studies of HPV-related koilocytes in breast cancer offer an opportunity to address this crucial issue. Koilocytes are epithelial cells characterised by perinuclear haloes surrounding condensed nuclei and are commonly present in cervical intraepithelial neoplasia. Koilocytosis is accepted as pathognomonic (characteristic of a particular disease) of HPV infection. The aim of this investigation is to determine whether putative koilocytes in normal and malignant breast tissues are because of HPV infection. METHODS: Archival formalin-fixed normal and malignant breast specimens were investigated by histology, in situ PCR with confirmation of the findings by standard PCR and sequencing of the products, plus immunohistochemistry to identify HPV E6 oncoproteins. RESULTS: human papilloma virus-associated koilocytes were present in normal breast skin and lobules and in the breast skin and cancer tissue of patients with ductal carcinoma in situ (DCIS) and invasive ductal carcinomas (IDCs). INTERPRETATION: As koilocytes are known to be the precursors of some HPV-associated cervical cancer, it follows that HPVs may be causally associated with breast cancer.
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ItemHuman papilloma virus is associated with breast cancer.(Springer Science and Business Media LLC, 2009-10-20)BACKGROUND: There is increasing evidence that high-risk human papilloma virus (HPV) is involved in cancers in addition to cervical cancer. For example, it is generally accepted that HPV has a role in a significant proportion of head and neck tumours, and it has long been hypothesised that hormone dependent oncogenic viruses, such as HPV may have causal roles in some human breast cancers. A number of reports have identified HPV DNA in breast tissue and breast cancer specimens, but these rely on standard polymerase chain reaction (PCR), which is criticised for its propensity for contamination. METHODS: We have used two different technologies, in situ and standard PCR (with sequencing), and histology based on light microscopy. RESULTS: We unambiguously demonstrate the presence of high-risk HPV in the cells of breast cancer specimens and breast cancer cell lines. In addition, we also show that the oncogenic characteristics of HPV associated breast cancer are very similar to HPV-associated cervical cancer. Specifically, that putative koilocytes are present in some HPV associated breast cancers. INTERPRETATION: The above observations indicate a likely causal role for high-risk HPV in human breast cancer and offer the possibility of primary prevention of some breast cancers by vaccination against HPV.