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Objectives Resveratrol ( trans-3,4′,5-trihydroxystilbene ( 1)) was previously shown to extend the lifespan of different model organisms. However, its pharmacological efficiency is controversially discussed. Therefore, the bioactivity of four newly synthesized stilbenes ( trans-3,5-dimethoxy-4-fluoro-4′-hydroxystilbene ( 3), trans-4′-hydroxy-3,4,5-trifluorostilbene ( 4), trans-2,5-dimethoxy-4′-hydroxystilbene ( 5), trans-2,4′,5-trihydroxystilbene ( 6)) was compared to ( 1) and pterostilbene ( trans-3,5-dimethoxy-4′-hydroxystilbene ( 2)) in the established model organism Caenorhabditis elegans. Methods Trolox equivalent antioxidant capacity ( TEAC), 2′,7′-dichlorofluorescein ( DCF), thermotolerance assays, C. elegans lifespan analyses. Key findings All compounds exert a strong in-vitro radical scavenging activity ( 6 > 1 > 5 > 2 = 3 = 4), but in vivo, only ( 3) and ( 6) reduce reactive oxygen species ( ROS) accumulation. Furthermore, ( 3) and ( 6) increased the mobility of aged nematodes and prolonged their mean lifespans, while these compounds decreased the thermal stress resistance. Using daf-16 (FoxO), skn-1 (Nrf2) and sir-2.1 (sirtuin) loss-of-function mutant strains, the in vivo antioxidant effects of compounds ( 3) and ( 6) were abolished, showing the necessity of these evolutionary highly conserved factors. However, short-time treatment with stilbenes ( 3) and ( 6) did not modulate the cellular localization of the transcription factors DAF-16 and SKN-1. Conclusion In contrast to resveratrol, the synthetic stilbene derivatives ( 3) and ( 6) increase the lifespan of C. elegans, rendering them promising candidates for pharmacological anti-ageing purposes. [ABSTRACT FROM AUTHOR]

Purpose: Trabectedin has shown preclinical synergy with immune checkpoint inhibitors in preclinical models., Patients and Methods: TRAMUNE is a phase Ib study investigating the combination of trabectedin with durvalumab through a dose escalation phase and two expansion cohorts, soft tissue sarcoma (STS) and ovarian carcinoma. Trabectedin was given at three dose levels (1 mg/m2, 1.2 mg/m2, and 1.5 mg/m2) on day 1, in combination with durvalumab, 1,120 mg on day 2, every 3 weeks. The primary endpoints were the recommended phase II dose (RP2D) of trabectedin combined with durvalumab and the objective response rate (ORR) as per RECIST 1.1. The secondary endpoints included safety, 6-month progression-free rate (PFR), progression-free survival (PFS), overall survival, and biomarker analyses., Results: A total of 40 patients were included (dose escalation, n = 9; STS cohort, n = 16; ovarian carcinoma cohort, n = 15, 80% platinum resistant/refractory). The most frequent toxicities were grade 1-2 fatigue, nausea, neutropenia, and alanine/aspartate aminotransferase increase. One patient experienced a dose-limiting toxicity at dose level 2. Trabectedin at 1.2 mg/m2 was selected as the RP2D. In the STS cohort, 43% of patients experienced tumor shrinkage, the ORR was 7% [95% confidence interval (CI), 0.2-33.9], and the 6-month PFR was 28.6% (95% CI, 8.4-58.1). In the ovarian carcinoma cohort, 43% of patients experienced tumor shrinkage, the ORR was 21.4% (95% CI, 4.7-50.8), and the 6-month PFR was 42.9% (95% CI, 17.7-71.1). Baseline levels of programmed death-ligand 1 expression and CD8-positive T-cell infiltrates were associated with PFS in patients with ovarian carcinoma., Conclusions: Combining trabectedin and durvalumab is manageable. Promising activity is observed in patients with platinum-refractory ovarian carcinoma. See related commentary by Digklia et al., p. 1745., (©2021 American Association for Cancer Research.)

Background: Soft-tissue sarcomas (STS) represent a heterogeneous group of rare tumors including more than 70 different histological subtypes. High throughput molecular analysis (next generation sequencing exome [NGS]) is a unique opportunity to identify driver mutations that can change the usual one-size-fits-all treatment paradigm to a patient-driven therapeutic strategy. The primary objective of the MULTISARC trial is to assess whether NGS can be conducted for a large proportion of metastatic STS participants within a reasonable time, and, secondarily to determine whether a NGS-guided therapeutic strategy improves participant's outcome., Methods: This is a randomized, multicentre, phase II/III trial inspired by the design of umbrella and biomarker-driven trials. The setting plans up to 17 investigational centres across France and the recruitment of 960 participants. Participants aged at least 18 years, with unresectable locally advanced and/or metastatic STS confirmed by the French sarcoma pathological reference network, are randomized according to 1:1 allocation ratio between the experimental arm "NGS" and the standard "No NGS". NGS will be considered feasible if (i) NGS results are available and interpretable, and (ii) a report of exome sequencing including a clinical recommendation from a multidisciplinary tumor board is provided to investigators within 7 weeks from reception of the samples on the biopathological platform. A feasibility rate of more than 70% is expected (null hypothesis: 70% versus alternative hypothesis: 80%). In terms of care, participants randomized in "No NGS" arm and who fail treatment will be able to switch to the NGS arm at the request of the investigator., Discussion: The MULTISARC trial is a prospective study designed to provide high-level evidence to support the implementation of NGS in routine clinical practice for advanced STS participants, on a large scale., Trial Registration: clinicaltrial.gov NCT03784014 ., (© 2021. The Author(s).)