A Phase-Ii Study of Sulofenur, a Novel Sulfonylurea, in Recurrent Epithelial Ovarian-Cancer

A total of 16 patients with recurrent epithelial ovarian cancer were treated with sulofenur (LY 186641), a novel oral sulfonylurea. All subjects had received previous chemotherapy. Anaemia occurred in all 16 patients, 14 of whom required a blood transfusion, and 2/16 patients received methylene blue for breathlessness due to methaemaglobinaemia. Treatment was discontinued in 2/16 cases due to rising liver enzyme values, which reverted to normal on cessation of the drug. There was no nausea or alopecia. Only two minor responses were seen. Plasma drug levels were insufficient to result in anti-tumour activity as extrapolated from animal data. Further studies that attempt to increase the bioavailability and improve the therapeutic index are warranted

Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer.

Injectable luteinizing hormone-releasing hormone agonists (e.g., leuprolide) are the standard agents for achieving androgen deprivation for prostate cancer despite the initial testosterone surge and delay in therapeutic effect. The efficacy and safety of relugolix, an oral gonadotropin-releasing hormone antagonist, as compared with those of leuprolide are not known. In this phase 3 trial, we randomly assigned patients with advanced prostate cancer, in a 2:1 ratio, to receive relugolix (120 mg orally once daily) or leuprolide (injections every 3 months) for 48 weeks. The primary end point was sustained testosterone suppression to castrate levels (<50 ng per deciliter) through 48 weeks. Secondary end points included noninferiority with respect to the primary end point, castrate levels of testosterone on day 4, and profound castrate levels (<20 ng per deciliter) on day 15. Testosterone recovery was evaluated in a subgroup of patients. A total of 622 patients received relugolix and 308 received leuprolide. Of men who received relugolix, 96.7% (95% confidence interval [CI], 94.9 to 97.9) maintained castration through 48 weeks, as compared with 88.8% (95% CI, 84.6 to 91.8) of men receiving leuprolide. The difference of 7.9 percentage points (95% CI, 4.1 to 11.8) showed noninferiority and superiority of relugolix (P<0.001 for superiority). All other key secondary end points showed superiority of relugolix over leuprolide (P<0.001). The percentage of patients with castrate levels of testosterone on day 4 was 56.0% with relugolix and 0% with leuprolide. In the subgroup of 184 patients followed for testosterone recovery, the mean testosterone levels 90 days after treatment discontinuation were 288.4 ng per deciliter in the relugolix group and 58.6 ng per deciliter in the leuprolide group. Among all the patients, the incidence of major adverse cardiovascular events was 2.9% in the relugolix group and 6.2% in the leuprolide group (hazard ratio, 0.46; 95% CI, 0.24 to 0.88). In this trial involving men with advanced prostate cancer, relugolix achieved rapid, sustained suppression of testosterone levels that was superior to that with leuprolide, with a 54% lower risk of major adverse cardiovascular events. (Funded by Myovant Sciences; HERO ClinicalTrials.gov number, NCT03085095.)

Transcriptomics of induced defense responses to greenbug aphid feeding in near isogenic wheat lines.

The greenbug aphid, Schizaphis graminum (Rondani) is an important cereal pest, periodically threatening wheat yields in the United States and around the world. The single dominant gene, Gb3-based resistance is highly durable against prevailing greenbug biotypes under field conditions; however, the molecular mechanisms of Gb3-mediated defense responses remain unknown. We used Affymetrix GeneChip Wheat Genome Arrays to investigate the transcriptomics of host defense responses upon greenbug feeding on resistant and susceptible bulks (RB and SB, respectively) derived from two near-isogenic lines. The study identified 692 differentially expressed transcripts and further functional classification recognized 122 transcripts that are putatively associated to mediate biotic stress responses. In RB, Gb3-mediated resistance resulted in activation of transmembrane receptor kinases and signaling-related transcripts involved in early signal transduction cascades. While in SB, transcripts mediating final steps in jasmonic acid biosynthesis, redox homeostasis, peroxidases, glutathione S-transferases, and notable defense-related secondary metabolites were induced. Also transcripts involved in callose and cell wall decomposition were elevated SB, plausibly to facilitate uninterrupted feeding operations. These results suggest that Gb3-mediated resistance is less vulnerable to cell wall modification and the data provides ample tools for further investigations concerning R gene based model of resistance