A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Activation of the PI3K/AKT/mTOR pathway through loss of phosphatase and tensin homolog (PTEN) occurs in approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition of the androgen receptor (AR) and AKT may be beneficial in mCRPC with PTEN loss. PATIENTS AND METHODS: mCRPC patients who previously failed abiraterone and/or enzalutamide, received escalating doses of AZD5363 (capivasertib) starting at 320 mg twice daily (b.i.d.) given 4 days on and 3 days off, in combination with enzalutamide 160 mg daily. The co-primary endpoints were safety/tolerability and determining the maximum tolerated dose and recommended phase II dose; pharmacokinetics, antitumour activity, and exploratory biomarker analysis were also evaluated. RESULTS: Sixteen patients were enrolled, 15 received study treatment and 13 were assessable for dose-limiting toxicities (DLTs). Patients were treated at 320, 400, and 480 mg b.i.d. dose levels of capivasertib. The recommended phase II dose identified for capivasertib was 400 mg b.i.d. with 1/6 patients experiencing a DLT (maculopapular rash) at this level. The most common grade ≥3 adverse events were hyperglycemia (26.7%) and rash (20%). Concomitant administration of enzalutamide significantly decreased plasma exposure of capivasertib, though this did not appear to impact pharmacodynamics. Three patients met the criteria for response (defined as prostate-specific antigen decline ≥50%, circulating tumour cell conversion, and/or radiological response). Responses were seen in patients with PTEN loss or activating mutations in AKT, low or absent AR-V7 expression, as well as those with an increase in phosphorylated extracellular signal-regulated kinase (pERK) in post-exposure samples. CONCLUSIONS: The combination of capivasertib and enzalutamide is tolerable and has antitumour activity, with all responding patients harbouring aberrations in the PI3K/AKT/mTOR pathway. CLINICAL TRIAL NUMBER: NCT02525068.

Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects.

Androgen receptor (AR) signaling is a critical pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. However, over time, most tumors become resistant to ADT. The view of castration-resistant prostate cancer (CRPC) has changed dramatically in the last several years. Progress in understanding the disease biology and mechanisms of castration resistance led to significant advancements and to paradigm shift in the treatment. Accumulating evidence showed that prostate cancers develop adaptive mechanisms for maintaining AR signaling to allow for survival and further evolution. The aim of this review is to summarize molecular mechanisms of castration resistance and provide an update in the development of novel agents and strategies to more effectively target the AR signaling pathway.

[Malfunctions of pacemakers]. / Les dysfonctionnements de pacemakers

No pacemaker is absolutely reliable : more or less threatening failures can be observed after implantation. Pacemaker runaway has completely disappeared. Sudden battery failure, intermittent or permanent, remains too frequent. Other incidents, less frequent or severe, are also reviewed. Failures are often isolated and sporadic, but can sometimes involve a complete manufacture series. It is a medical duty to follow-up carefully the patients and to announce the failures with a view to permit early recognition of imperfect series. Pacing failures do not play a major role in the mortality in the group of patients with permanently implanted pacemakers. Nevertheless, anticipated replacement of pacemakers increases the cost of the technique.

[Bitachycardia]. / Les bitachycardies.

One or several episodes of bitachycardia (a simultaneous ventricular tachycardia and atrial tachycardia or fibrillation) were observed in 13 patients. An oesophageal or right atrial endocavitary recording is usually necessary to show the atrioventricular dissociation: even then the diagnosis may be difficult in cases of isorhythmic dissociation or when the ventricular tachycardia is irregular. In 5 cases the double tachycardia appeared to be coincidental. In 7 patients the ventricular tachycardia seemed to be dependant on the atrial tachycardia and could be initiated by a simple spontaneous atrial extrasystole in 3 cases. In one patient the ventricular tachycardia, after a phase of retrograde conduction to the atria, initiated the atrial arrhythmia. The therapeutic indications depend in part on the eventual relationship between the two arrhythmias.

[Paroxysmal block in phase 4 of the bundle of His]. / Les blocs paroxystiques en phase 4 dans le tronc du faisceau de His.

Five cases of chronic paroxysmal atrio-ventricular block are reported, being unusual in the siting of the conduction defect within the trunk of the bundle of His, and in the "paradoxical" mode of onset of the block. The ventriculograms which were carried out, and the escapes, were of normal duration in four cases and the intracavitary recordings showed a double His potential in all patients. In one case, the block during phase 4 seemed to occur at the height of the trunkal Wenkebach periods, and in another it could be brought on by manipulation of the vagus. In all five cases, a favorable conduction zone could be calculated, the block to the P waves in phase 4 occuring in an arithmetical fashion after a critical lengthening of the PR interval. The return to sinus rhythm was always related to an escape (or to an electrically induced ventricular complex), but the explanation of the initial capture on electrophysiological grounds is obscure.

[Action of injected disopyramide on ventricular arrhythmias and atrioventricular conduction]. / Action du Disopyramide injectable sur les arythmies ventriculaires et sur la conduction auriculo-ventriculaire

The authors have studied the bathmotropic and dromotropic effects of intravenous injection of 100 mg of disopyramide, the therapeutic dose being 1 to 2 mg/kg. Out of the 28 severe arrhythmias studied, it was the ventricular extrasystoles which benefited most from treatment (79% completely successful, while there was a lesser degree of success in treating the ventricular tachycardias (35% completely successful, 30% partially successful). The negative dromotropic effect of injected disopyramide on sub-nodal conduction was studied by an endocavitary technique in 10 patients presenting with a spontaneous onset of disordered intracardiac conduction; the effects were moderate. With the exception of 4 cases who sustained complications involving rhythm and haemodynamics, the clinical and cardiovascular tolerance of patients to the drug appeared to be satisfactory.

Shopping for health care.

All political parties have now published their manifestos. Of course, the content of these documents will have been planned and refined over a period of months.

Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib.

The vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor sunitinib has been approved for first-line treatment of patients with metastatic renal cancer and is currently being trialled in other cancers. However, the effectiveness of this anti-angiogenic agent is limited by the presence of innate and acquired drug resistance. By screening a panel of candidate growth factors we identified fibroblast growth factor 2 (FGF2) as a potent regulator of endothelial cell sensitivity to sunitinib. We show that FGF2 supports endothelial proliferation and de novo tubule formation in the presence of sunitinib and that FGF2 can suppress sunitinib-induced retraction of tubules. Importantly, these effects of FGF2 were ablated by PD173074, a small molecule inhibitor of FGF receptor signalling. We also show that FGF2 can stimulate pro-angiogenic signalling pathways in endothelial cells despite the presence of sunitinib. Finally, analysis of clinical renal-cancer samples demonstrates that a large proportion of renal cancers strongly express FGF2. We suggest that therapeutic strategies designed to simultaneously target both VEGF and FGF2 signalling may prove more efficacious than sunitinib in renal cancer patients whose tumours express FGF2.