Overview of the Development and Use of Akt Inhibitors in Prostate Cancer

Deregulation of the PI3K-Akt-mTOR pathway plays a critical role in the development and progression of many cancers. In prostate cancer, evidence suggests that it is mainly driven by PTEN loss of function. For many years, the development of selective Akt inhibitors has been challenging. In recent phase II and III clinical trials, Ipatasertib and Capivasertib associated with androgen deprivation therapies showed promising outcomes in patients with metastatic castration-resistant prostate cancer and PTEN-loss. Ongoing trials are currently assessing several Akt inhibitors in prostate cancer with different combinations, at different stages of the disease.

Factorbook: an Updated Catalog of Transcription Factor Motifs and Candidate Regulatory Motif Sites

ABSTRACTThe human genome contains roughly 1,600 transcription factors (TFs) (1), DNA-binding proteins recognizing characteristic sequence motifs to exert regulatory effects on gene expression. The binding specificities of these factors have been profiled both in vitro, using techniques such as HT-SELEX (2), and in vivo, using techniques including ChIP-seq (3, 4). We previously developed Factorbook, a TF-centric database of annotations, motifs, and integrative analyses based on ChIP-seq data from Phase II of the ENCODE Project. Here we present an update to Factorbook which significantly expands the breadth of cell type and TF coverage. The update includes an expanded motif catalog derived from thousands of ENCODE Phase II and III ChIP-seq experiments and HT-SELEX experiments; this motif catalog is integrated with the ENCODE registry of candidate cis-regulatory elements to annotate a comprehensive collection of genome-wide candidate TF binding sites. The database also offers novel tools for applying the motif models within machine learning frameworks and using these models for integrative analysis, including annotation of variants and disease and trait heritability. We will continue to expand the resource as ENCODE Phase IV data are released.

Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey

GPR40 (FFAR1) is a promising target for the managing type 2 diabetes (T2D). The most advanced GPR40 agonist TAK-875 exhibited satisfactory glucose-lowering effects in phase II and III studies. However, the phase III studies of TAK-875 revealed drug-induced liver injury (DILI). It is unknown whether DILI is a consequence of a specific GPR40 agonist or is an inherent feature of all GPR40 agonists. CPL207280 is a novel GPR40 agonist that improves diabetes in Zucker Diabetic Fatty (ZDF) rats, Goto Kakizaki (GK) rats and db/db mice. In this report, the DILI-related toxicity of CPL207280 was compared directly with that of TAK-875. In vitro studies evaluating hepatic biliary transporter inhibition, mitochondrial function, and metabolic profiling were performed in hepatocytes from different species. The long term toxicity of CPL207280 was studied in vivo in rats and monkeys. Activity of CPL207280 was one order of magnitude lesser than that of TAK-875 for the inhibition of bile acid transporters. CPL207280 had a negligible effect on the hepatic mitochondria. In contrast to TAK-875, which was metabolized through toxic glucuronidation, CPL207280 was metabolized mainly through oxidation. No deleterious hepatic effects were observed in chronically treated healthy and diabetic animals. The study presents promising data on the feasibility of creating a liver-safe GPR40 agonist. Additionally, it can be concluded that DILI is not a hallmark of GPR40 agonists; it is linked to the intrinsic properties of an individual agonist.

Glaucoma Clinical Research: Trends in Treatment Strategies and Drug Development

Purpose: To investigate the trends and progresses in glaucoma research by searching two major clinical trial registries; clinicaltrials.gov, and Australianclinicaltrials.gov.au.Methods: All clinical trials with glaucoma covered by Clinicaltrials.gov, and Australianclinicaltrials.gov.au starting the study before 1 January 2021 were included. Trials evaluating glaucoma treatment were separated from non-treatment trials and divided into three major categories: “laser treatment,” “surgical treatment,” and “medical treatment.” In the category of “medical treatment,” new compounds and their individual targets were identified and subcategorized according to treatment strategy; intraocular pressure (IOP)-lowering, neuroprotective or vascular. The phase transition success rates were calculated.Results: One-thousand five hundred and thirty-seven trials were identified. Sixty-three percent (n = 971) evaluated glaucoma treatment, of which medical treatment accounted for the largest proportion (53%). The majority of medical trials evaluated IOP-lowering compounds, while trials with neuroprotective or vascular compounds accounted for only 5 and 3%, respectively. Eighty-eight new compounds were identified. Phase I, II, and III transition success rates were 63, 26, and 47%, respectively.Conclusion: The number of clinical trials in glaucoma research has increased significantly over the last 30 years. Among the most recently evaluated compounds, all three main treatment strategies were represented, but clinical trials in neuroprotection and vascular modalities are still sparse. In addition to traditional medicines, dietary supplements and growth factors are assessed for a potential anti-glaucomatous effect. Phase II and III success rates were below previously reported success rates for all diseases and ophthalmology in general. A stricter phenotyping of patients can improve the success rates in glaucoma and ophthalmological research and gain a better understanding of responders and non-responders.

681 PATTERN OF RECURRENCE IN PATIENTS WITH A PATHOLOGICALLY COMPLETE RESPONSE AFTER NEOADJUVANT CHEMORADIOTHERAPY AND SURGERY FOR OESOPHAGEAL CANCER

Neoadjuvant chemoradiotherapy (nCRT) and surgery is a widely used treatment for locally advanced resectable oesophageal cancer, with 20 and 50% of patients having a pathological complete response (pCR). Disease, however, still recurs in 20–30% of these patients. The aim of this study was to assess the pattern of recurrence in patients with pCR after nCRT and surgery. Methods All patients with pCR after neoadjuvant chemoradiotherapy and surgery included in the phase II and III ChemoRadiotherapy for Oesophageal followed by Surgery Study (CROSS) trials (April 2001—March 2009) and after the CROSS trials (September 2009—October 2017) were identified. The site of recurrence was compared to the applied radiation and surgical fields. Outcomes were median time to recurrence, overall and progression-free survivals. Results A total of 141 patients with a median follow-up of 100 (interquartile range [IQR] 64–134) months were included. Some 29 of 141 patients (21%) developed recurrence. Of these, four (14%) had isolated locoregional recurrence, 15 (52%) distant recurrence only and ten (34%) had both locoregional and distant recurrence. Among the 14 patients with locoregional recurrences, five were within the radiation field, seven outside the radiation field and two at the border. Median (IQR) time to recurrence was 24 (10–62) months. The 5-year overall survival was 74% and recurrence-free survival 70%. Conclusion Despite good overall survival, recurrence still occurred in 21% of patients. Most recurrences were distant, outside the radiation and surgical fields.

Tapentadol in acute pain: a review of the results of international studies

The treatment of acute pain is a fundamental goal for doctors of various specialties. Tapentadol, which combines the properties of an opioid receptor agonist and a noradrenalin reuptake inhibitor, is one of the most popular analgesics in the world that is effective in severe acute pain. We provide a review of international publications about pharmacological properties, efficacy and safety of tapentadol immediate release (IR) in acute pain. Data from phase II and III of randomized controlled trials (RCTs), in which tapentadol IR (50, 75 and 100 mg) was used for moderate to severe pain in surgical and therapeutic practice is discussed. A number of studies have compared tapentadol with placebo groups and classical opioids (oxycodone, morphine). The results of two meta-analyzes and systematic reviews of efficacy and safety of this analgesic in patients with acute pain are presented.International multicenter RCTs have demonstrated high efficacy of tapentadol IR 50, 75 and 100 mg in patients in the early postoperative period. Comparison with other opioid analgesics showed that tapentadol was superior to placebo and comparable to oxycodone in analgesic effect.It was concluded that tapentadol has a better safety and tolerability profile than classical opioids. The incidence of adverse events on this drug is lower than on oxycodone or morphine.