Hormone-sensitive prostate cancer: a case of ETS gene fusion heterogeneity.

Fusion of the hormone-regulated gene TMPRSS2 with ERG occurs in 50-70% of prostate cancers; fusions of ETV1 with one of several partners occur in approximately 10% of prostate cancers. These two translocations are mutually exclusive. The presence of subclasses of these chromosomal rearrangements may indicate worse prognosis, with the subclass 2+Edel, which has duplication of TMPRSS2:ERG fusion sequences, indicating particularly poor survival.

Integration of ERG gene mapping and gene-expression profiling identifies distinct categories of human prostate cancer.

Objective: To integrate the mapping of ERG alterations with the collection of expression microarray (EMA) data, as previous EMA analyses have failed to consider the genetic heterogeneity and complex patterns of ERG alteration frequently found in cancerous prostates.

Materials And Methods: We determined genome-wide expression levels with GeneChip Human Exon 1.0 ST arrays (Affymetrix, Santa Clara, CA, USA) using RNA prepared from 35 specimens of prostate cancer from 28 prostates.

CYP17 inhibition as a hormonal strategy for prostate cancer.

Androgen receptor (AR) signaling has a key role in the pathogenesis of prostate cancer. AR gene amplification, AR overexpression, and activating mutations in the AR occur more frequently as castration-resistant prostate cancer (CRPC) evolves, with intratumoral androgen levels remaining sufficient for AR activation despite castration. The source of these androgens might be either adrenal or intratumoral.

Cationic type I amphiphiles as modulators of membrane curvature elastic stress in vivo.

Recently we proposed that the antineoplastic properties observed in vivo for alkyl-lysophospholipid and alkylphosphocholine analogues are a direct consequence of the reduction of membrane stored elastic stress induced by these amphiphiles. Here we report similar behavior for a wide range of cationic surfactant analogues. Our systematic structure-activity studies show that the cytotoxic properties of cationic surfactants follow the same pattern of activity we observed previously for alkyl-lysophospholipid analogues, indicating a common mechanism of action that is consistent with the theory that these amphiphiles reduce membrane stored elastic stress.

Circulating tumour cell (CTC) counts as intermediate end points in castration-resistant prostate cancer (CRPC): a single-centre experience.

Background: The purpose of this study was to evaluate the association of circulating tumour cell (CTC) counts, before and after commencing treatment, with overall survival (OS) in patients with castration-resistant prostate cancer (CRPC).

Experimental Design: A 7.5 ml of blood was collected before and after treatment in 119 patients with CRPC.

Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven.

Purpose: Studies indicate that castration-resistant prostate cancer (CRPC) remains driven by ligand-dependent androgen receptor (AR) signaling. To evaluate this, a trial of abiraterone acetate-a potent, selective, small-molecule inhibitor of cytochrome P (CYP) 17, a key enzyme in androgen synthesis-was pursued.

Patients And Methods: Chemotherapy-naïve men (n = 21) who had prostate cancer that was resistant to multiple hormonal therapies were treated in this phase I study of once-daily, continuous abiraterone acetate, which escalated through five doses (250 to 2,000 mg) in three-patient cohorts.

Targeting CYP17: established and novel approaches in prostate cancer.

There is a growing body of evidence that although medical or surgical castration blocks the generation of gonadal testosterone in prostate cancer, androgens originating from other sources may continue to drive androgen receptor (AR) signaling. Recent studies have demonstrated high intratumoral levels of androgens and continued AR signaling in castration-resistant prostate cancer (CRPC), suggesting that androgens may also be synthesized de novo. Inhibiting the systemic biosynthesis of androgens in CRPC by targeting CYP17 may thus represent a rational therapeutic approach since this enzyme catalyses two key steroid reactions involving 17alpha-hydroxylase and C(17,20)-lyase in the androgen biosynthesis pathway.

Heterogeneity and clinical significance of ETV1 translocations in human prostate cancer.

A fluorescence in situ hybridisation (FISH) assay has been used to screen for ETV1 gene rearrangements in a cohort of 429 prostate cancers from patients who had been diagnosed by trans-urethral resection of the prostate. The presence of ETV1 gene alterations (found in 23 cases, 5.4%) was correlated with higher Gleason Score (P=0.

Dissecting prostate carcinogenesis through ETS gene rearrangement studies: implications for anticancer drug development.

The discovery of ETS gene fusions as common events in prostate cancer represents a paradigmatic shift in the significance attributed to chromosomal translocations as a key mechanistic player in carcinogenesis. However, these chromosomal fusion events are poorly understood, as their functional significance and therapeutic potential remain unclear. Nonetheless, they have generally been used as novel molecular handles to sub-categorise the broad diversity of prostate cancers mainly via the use of fluorescence in-situ hybridisation-based "break-apart assays".

DNA that is dispersed in the liquid crystalline phases of phospholipids is actively transcribed.

We report that a 4.3 kbp linearised T7 DNA plasmid is actively transcribed when it is dispersed in the hexagonal liquid crystalline phase of dioleoylphosphoethanolamine (DOPE).

Testing the hypothesis that amphiphilic antineoplastic lipid analogues act through reduction of membrane curvature elastic stress.

The alkyllysophospholipid (ALP) analogues Mitelfosine and Edelfosine are anticancer drugs whose mode of action is still the subject of debate. It is agreed that the primary interaction of these compounds is with cellular membranes. Furthermore, the membrane-associated protein CTP: phosphocholine cytidylyltransferase (CCT) has been proposed as the critical target.

Expression profiling of CD133+ and CD133- epithelial cells from human prostate.

Background: Recent evidence suggests that prostate stem cells in benign and tumor tissue express the cell surface marker CD133, but these cells have not been well characterized. The aim of our study was to gene expression profile CD133-expressing cells.

Methods: We analyzed CD133-positive (CD133+) and -negative (CD133-) sub-populations of high-integrin expressing epithelial cells isolated from benign human prostate tissue and hormone-refractory prostate cancer (HRPC).

Kawasaki disease presenting as hepatitis.

Kawasaki disease (KD) presenting with an acute hepatitic picture is exceedingly rare. A 3.5-year-old girl presented with acute hepatitis and went on to satisfy the criteria for the diagnosis of KD for which she was treated.

A phase Ib study of pertuzumab, a recombinant humanised antibody to HER2, and docetaxel in patients with advanced solid tumours.

Pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerisation inhibitors. We conducted a phase Ib study to determine the maximum-tolerated dose, the dose limiting toxicities (DLT), and pharmacokinetic (PK) interaction of docetaxel when administered in combination with pertuzumab. Initially, two dose levels of docetaxel (60 and 75 mg m(-2)) were explored in combination with a fixed dose of 1050 mg of pertuzumab; then two dose levels of docetaxel (75 and 100 mg m(-2)) were explored in combination following a fixed dose of 420 mg of pertuzumab with a loading dose of 840 mg.

Phase 1 and pharmacokinetic study of lexatumumab in patients with advanced cancers.

Purpose: To assess the safety and tolerability, pharmacokinetics, and early evidence of antitumor activity of escalating doses of lexatumumab (HGS-ETR2), a fully human agonistic monoclonal antibody which targets and activates the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) in patients with advanced solid malignancies.

Experimental Design: In this phase 1, open label study, patients with advanced solid malignancies were treated with escalating doses of lexatumumab administered i.v.

Integrative feedback and robustness in a lipid biosynthetic network.

The homeostatic control of membrane lipid composition appears to be of central importance for cell functioning and survival. However, while lipid biosynthetic reaction networks have been mapped in detail, the underlying control architecture which underpins these networks remains elusive. A key problem in determining the control architectures of lipid biosynthetic pathways, and the mechanisms through which control is achieved, is that the compositional complexity of lipid membranes makes it difficult to determine which membrane parameter is under homeostatic control.

Complex patterns of ETS gene alteration arise during cancer development in the human prostate.

An ERG gene 'break-apart' fluorescence in situ hybridization (FISH) assay has been used to screen whole-mount prostatectomy specimens for rearrangements at the ERG locus. In cancers containing ERG alterations the observed pattern of changes was often complex. Different categories of ERG gene alteration were found either together in a single cancerous region or within separate foci of cancer in the same prostate slice.

Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer.

New predictive markers for managing prostate cancer are urgently required because of the highly variable natural history of this disease. At the time of diagnosis, Gleason score provides the gold standard for assessing the aggressiveness of prostate cancer. However, the recent discovery of TMPRSS2 fusions to the ERG gene in prostate cancer raises the possibility of using alterations at the ERG locus as additional mechanism-based prognostic indicators.

Potential applications for circulating tumor cells expressing the insulin-like growth factor-I receptor.

Purpose: To detect insulin-like growth factor-IR (IGF-IR) on circulating tumor cells (CTC) as a biomarker in the clinical development of a monoclonal human antibody, CP-751,871, targeting IGF-IR.

Experimental Design: An automated sample preparation and analysis system for enumerating CTCs (CellTracks) was adapted for detecting IGF-IR-positive CTCs with a diagnostic antibody targeting a different IGF-IR epitope to CP-751,871. This assay was used in three phase I trials of CP-751,871 as a single agent or with chemotherapy and was validated using cell lines and blood samples from healthy volunteers and patients with metastatic carcinoma.

Probing phospholipid dynamics by electrospray ionisation mass spectrometry.

Recent advances in electrospray ionisation mass spectrometry (ESI-MS) have greatly facilitated the analysis of phospholipid molecular species in a growing diversity of biological and clinical settings. The combination of ESI-MS and metabolic labelling employing substrates labelled with stable isotopes is especially exciting, permitting studies of phospholipid synthesis and turnover in vivo. This review will first describe the methodology involved and will then detail dynamic lipidomic studies that have applied the stable isotope incorporation approach.

Using membrane stress to our advantage.

The nature of the bilayer motif coupled with the ability of lipids and proteins to diffuse freely through this structure is crucial to the viability of cells and their ability to compartmentalize domains contained therein. It seems surprising to find then that biological as well as model membranes exist in a dynamic state of mechanical stress. The stresses within such membranes are surprisingly large, typically reaching up to 50 atm (1 atm=101.

Open-label phase II study evaluating the efficacy and safety of two doses of pertuzumab in castrate chemotherapy-naive patients with hormone-refractory prostate cancer.

Purpose: To determine the prostate-specific antigen (PSA) 50% decline rate within 24 weeks of starting treatment with single-agent pertuzumab in castrate patients with hormone-refractory prostate cancer (HRPC).

Patients And Methods: Two independent Simon's two-stage designs were used to evaluate two doses of pertuzumab administered intravenously once every 3 weeks. An interim analysis of the first 23 assessable patients in the first cohort treated at 420 mg (loading dose of 840 mg) allowed termination of additional enrollment if three patients had a 50% decline in PSA after all patients had completed at least three cycles of therapy or withdrew due to insufficient therapeutic response, death, or study-related toxicity before completing three cycles.

Improving the outcome of patients with castration-resistant prostate cancer through rational drug development.

Castration-resistant prostate cancer (CRPC) is now the second most common cause of male cancer-related mortality. Although docetaxel has recently been shown to extend the survival of patients with CRPC in two large randomised phase III studies, subsequent treatment options remain limited for these patients. A greater understanding of the molecular causes of castration resistance is allowing a more rational approach to the development of new drugs and many new agents are now in clinical development.