Sir Peter MacCallum Department of Oncology - Research Publications
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ItemUnproven medical devices and cancer therapy: big claims but no evidence.(Department of Biomedical Imaging, University of Malaya, Malaysia, 2008-07)
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ItemExpanded risk groups help determine which prostate radiotherapy sub-group may benefit from adjuvant androgen deprivation therapy(BMC, 2008-04-18)PURPOSE: To assess whether an expanded (five level) risk stratification system can be used to identify the sub-group of intermediate risk patients with prostate cancer who benefit from combining androgen deprivation therapy (ADT) with external beam radiotherapy (EBRT). MATERIALS AND METHODS: Using a previously validated 5-risk group schema, a prospective non-randomized data set of 1423 men treated at the British Columbia Cancer Agency was assessed for the primary end point of biochemical control (bNED) with the RTOG-ASTRO "Phoenix" definition (lowest PSA to date + 2 ng/mL), both with and without adjuvant ADT. The median follow-up was 5 years. RESULTS: There was no bNED benefit for ADT in the low or low intermediate groups but there was a statistically significant bNED benefit in the high intermediate, high and extreme risk groups. The 5-year bNED rates with and without ADT were 70% and 73% respectively for the low intermediate group (p = non-significant) and 72% and 58% respectively for the high intermediate group (p = 0.002). CONCLUSION: There appears to be no advantage to ADT where the Gleason score is 6 or less and PSA is 15 or less. ADT is beneficial in patients treated to standard dose radiation with Gleason 6 disease and a PSA greater than 15 or where the Gleason score is 7 or higher.
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ItemTumor-Specific Hsp70 Plasma Membrane Localization Is Enabled by the Glycosphingolipid Gb3(PUBLIC LIBRARY SCIENCE, 2008-04-02)BACKGROUND: Human tumors differ from normal tissues in their capacity to present Hsp70, the major stress-inducible member of the HSP70 family, on their plasma membrane. Membrane Hsp70 has been found to serve as a prognostic indicator of overall patient survival in leukemia, lower rectal and non small cell lung carcinomas. Why tumors, but not normal cells, present Hsp70 on their cell surface and the impact of membrane Hsp70 on cancer progression remains to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: Although Hsp70 has been reported to be associated with cholesterol rich microdomains (CRMs), the partner in the plasma membrane with which Hsp70 interacts has yet to be identified. Herein, global lipid profiling demonstrates that Hsp70 membrane-positive tumors differ from their membrane-negative counterparts by containing significantly higher amounts of globotriaoslyceramide (Gb3), but not of other lipids such as lactosylceramide (LacCer), dodecasaccharideceramide (DoCer), galactosylceramide (GalCer), ceramide (Cer), or the ganglioside GM1. Apart from germinal center B cells, normal tissues are Gb3 membrane-negative. Co-localization of Hsp70 and Gb3 was selectively determined in Gb3 membrane-positive tumor cells, and these cells were also shown to bind soluble Hsp70-FITC protein from outside in a concentration-dependent manner. Given that the latter interaction can be blocked by a Gb3-specific antibody, and that the depletion of globotriaosides from tumors reduces the amount of membrane-bound Hsp70, we propose that Gb3 is a binding partner for Hsp70. The in vitro finding that Hsp70 predominantly binds to artificial liposomes containing Gb3 (PC/SM/Chol/Gb3, 17/45/33/5) confirms that Gb3 is an interaction partner for Hsp70. CONCLUSIONS/SIGNIFICANCE: These data indicate that the presence of Gb3 enables anchorage of Hsp70 in the plasma membrane of tumors and thus they might explain tumor-specific membrane localization of Hsp70.
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ItemDNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors(ROCKEFELLER UNIV PRESS, 2008-12-22)Natural killer (NK) cells and CD8 T cells require adhesion molecules for migration, activation, expansion, differentiation, and effector functions. DNAX accessory molecule 1 (DNAM-1), an adhesion molecule belonging to the immunoglobulin superfamily, promotes many of these functions in vitro. However, because NK cells and CD8 T cells express multiple adhesion molecules, it is unclear whether DNAM-1 has a unique function or is effectively redundant in vivo. To address this question, we generated mice lacking DNAM-1 and evaluated DNAM-1-deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require DNAM-1 for co-stimulation when recognizing antigen presented by nonprofessional antigen-presenting cells; in contrast, DNAM-1 is dispensable when dendritic cells present the antigen. Similarly, NK cells require DNAM-1 for the elimination of tumor cells that are comparatively resistant to NK cell-mediated cytotoxicity caused by the paucity of other NK cell-activating ligands. We conclude that DNAM-1 serves to extend the range of target cells that can activate CD8 T cell and NK cells and, hence, may be essential for immunosurveillance against tumors and/or viruses that evade recognition by other activating or accessory molecules.
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ItemSafety and pharmacokinetics of motesanib in combination with gemcitabine for the treatment of patients with solid tumours(NATURE PUBLISHING GROUP, 2008-10-28)The aim of this open-label phase 1b study was to assess the safety and pharmacokinetics of motesanib in combination with gemcitabine in patients with advanced solid tumours. Eligible patients with histologically or cytologically documented solid tumours or lymphoma were enroled in three sequential, dose-escalating cohorts to receive motesanib 50 mg once daily (QD), 75 mg two times daily (BID), or 125 mg QD in combination with gemcitabine (1000 mg m(-2)). The primary end point was the incidence of dose-limiting toxicities (DLTs). Twenty-six patients were enroled and received motesanib and gemcitabine. No DLTs occurred. The 75 mg BID cohort was discontinued early; therefore, 125 mg QD was the maximum target dose. Sixteen patients (62%) experienced motesanib-related adverse events, most commonly lethargy (n=6), diarrhoea (n=4), fatigue (n=3), headache (n=3), and nausea (n=3). The pharmacokinetics of motesanib and of gemcitabine were not markedly affected after combination therapy. The objective response rate was 4% (1 of 26), and 27% (7 of 26) of patients achieved stable disease. In conclusion, treatment with motesanib plus gemcitabine was well tolerated, with adverse event and pharmacokinetic profiles similar to that observed in monotherapy studies.
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ItemRandomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer(NATURE PUBLISHING GROUP, 2008-12-09)ASA404 (5,6-dimethylxanthenone-4-acetic acid or DMXAA) is a small-molecule tumour-vascular disrupting agent (Tumour-VDA). This randomised phase II study evaluated ASA404 plus standard therapy of carboplatin and paclitaxel in patients with histologically confirmed stage IIIb or IV non-small cell lung cancer (NSCLC) not previously treated with chemotherapy. Patients were randomised to receive
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ItemNo Preview AvailableA rational approach to cancer therapy.(Springer Science and Business Media LLC, 2008)A report on the 20th Annual Lorne Cancer Conference, Lorne, Australia, 14-16 February 2008.
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ItemNo Preview AvailableThe MACPF/CDC family of pore-forming toxins(WILEY, 2008-09)Pore-forming toxins (PFTs) are commonly associated with bacterial pathogenesis. In eukaryotes, however, PFTs operate in the immune system or are deployed for attacking prey (e.g. venoms). This review focuses upon two families of globular protein PFTs: the cholesterol-dependent cytolysins (CDCs) and the membrane attack complex/perforin superfamily (MACPF). CDCs are produced by Gram-positive bacteria and lyse or permeabilize host cells or intracellular organelles during infection. In eukaryotes, MACPF proteins have both lytic and non-lytic roles and function in immunity, invasion and development. The structure and molecular mechanism of several CDCs are relatively well characterized. Pore formation involves oligomerization and assembly of soluble monomers into a ring-shaped pre-pore which undergoes conformational change to insert into membranes, forming a large amphipathic transmembrane beta-barrel. In contrast, the structure and mechanism of MACPF proteins has remained obscure. Recent crystallographic studies now reveal that although MACPF and CDCs are extremely divergent at the sequence level, they share a common fold. Together with biochemical studies, these structural data suggest that lytic MACPF proteins use a CDC-like mechanism of membrane disruption, and will help understand the roles these proteins play in immunity and development.
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ItemNo Preview AvailableChromatin organization and expression.(Springer Science and Business Media LLC, 2008-04-14)A report on the 29th Lorne Genome Conference on the Organization and Expression of the Genome, Lorne, Australia, 17-21 February 2008.
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ItemA novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation(ROCKEFELLER UNIV PRESS, 2008-01-28)Like Bcl-2, Mcl-1 is an important survival factor for many cancers, its expression contributing to chemoresistance and disease relapse. However, unlike other prosurvival Bcl-2-like proteins, Mcl-1 stability is acutely regulated. For example, the Bcl-2 homology 3 (BH3)-only protein Noxa, which preferentially binds to Mcl-1, also targets it for proteasomal degradation. In this paper, we describe the discovery and characterization of a novel BH3-like ligand derived from Bim, Bim(S)2A, which is highly selective for Mcl-1. Unlike Noxa, Bim(S)2A is unable to trigger Mcl-1 degradation, yet, like Noxa, Bim(S)2A promotes cell killing only when Bcl-x(L) is absent or neutralized. Furthermore, killing by endogenous Bim is not associated with Mcl-1 degradation. Thus, functional inactivation of Mcl-1 does not always require its elimination. Rather, it can be efficiently antagonized by a BH3-like ligand tightly engaging its binding groove, which is confirmed here with a structural study. Our data have important implications for the discovery of compounds that might kill cells whose survival depends on Mcl-1.