Gastric carcinomas (GC) are heterogeneous tumors, composed of a subpopulation of cluster of differentiation‐44 (CD44)+ tumorigenic and chemoresistant cancer stem cells (CSC). YAP1 and TAZ ...oncoproteins (Y/T) interact with TEA domain family member 1 (TEAD) transcription factors to promote cell survival and proliferation in multiple tissues. Their activity and role in GC remain unclear. This work aimed to analyze Y/T‐TEAD activity and molecular signature in gastric CSC, and to assess the effect of verteporfin, a Food and Drug Administration‐approved drug preventing Y/T‐TEAD interaction, on gastric CSC tumorigenic properties. Y/T‐TEAD molecular signature was investigated using bioinformatical (KmPlot database), transcriptomic and immunostaining analyses in patient‐derived GC and cell lines. Verteporfin effects on Y/T‐TEAD transcriptional activity, CSC proliferation and tumorigenic properties were evaluated using in vitro tumorsphere assays and mouse models of patient‐derived GC xenografts. High expressions of YAP1, TAZ, TEAD1, TEAD4 and their target genes were associated with low overall survival in nonmetastatic human GC patients (n = 444). This Y/T‐TEAD molecular signature was enriched in CD44+ patient‐derived GC cells and in cells resistant to conventional chemotherapy. Verteporfin treatment inhibited Y/T‐TEAD transcriptional activity, cell proliferation and CD44 expression, and decreased the pool of tumorsphere‐forming CD44+/aldehyde dehydrogenase (ALDH)high gastric CSC. Finally, verteporfin treatment inhibited GC tumor growth in vivo; the residual tumor cells exhibited reduced expressions of CD44 and ALDH1, and more importantly, they were unable to initiate new tumorspheres in vitro. All these data demonstrate that Y/T‐TEAD activity controls gastric CSC tumorigenic properties. The repositioning of verteporfin targeting YAP1/TAZ‐TEAD activity could be a promising CSC‐based strategy for the treatment of GC.
What's new?
In gastric cancer, populations of cancer stem cells (CSCs), which initiate and sustain tumor growth and drive tumor recurrence, are maintained through activity of the yes‐associated protein 1 (YAP1), TAZ, and TEA domain transcription factor (TEAD) complex. In this study, employing gastric cancer models, transcriptional activity of the YAP1/TAZ‐TEAD complex was successfully inhibited by the benzoporphyrin derivative verteporfin. Specifically, verteporfin decreased the pool of gastric CSCs in vitro and in vivo and inhibited tumor growth in patient‐derived gastric cancer xenografts. The results suggest that targeting YAP1/TAZ‐TEAD activity with verteporfin is a promising therapeutic strategy for gastric cancer.
Hydrogels are soft materials of the utmost importance in the biomedical and healthcare fields. Two approaches can be considered to obtain such biomaterials: the macromolecular one and the ...supramolecular one. In the first, the chemical gel is based on crosslinking while in the second the physical hydrogel is stabilized thanks to noncovalent interactions. Recently, new trends rely on smart devices able to modify their physico-chemical properties under stimulation. Such stimuli-responsive systems can react to internal (i.e. pH, redox potential, enzyme, etc.) or external (i.e. magnetic field, light, electric field, etc.) triggers leading to smart drug release and drug delivery systems, 3D scaffolds or biosensors. Even if some stimuli-responsive biomaterials are currently widely studied, other ones represent a real challenge. Among them, electro-responsive hydrogels, especially obtained via supramolecular approach, are under-developped leaving room for improvement. Indeed, currently known macromolecular electro-responsive systems are reaching some limitations related to their chemical composition, physicochemical properties, mechanical strength, processing technologies, etc. In contrast, the interest for supramolecular hydrogels has risen for the past few years suggesting that they may provide new solutions as electro-responsive soft materials. In this short review, we give a recent non exhaustive survey on macromolecular and supramolecular approaches for electro-responsive hydrogels in the biomedical field.
Hybrid synthetic amphiphilic biomolecules are emerging as promising supramolecular materials for biomedical and technological applications. Herein, recent progress in the field of nucleic acid based ...lipids is highlighted with an emphasis on their molecular design, synthesis, supramolecular properties, physicochemical behaviors, and applications in the field of health science and technology. In the first section, the design and the study of nucleolipids are in focus and then the glyconucleolipid family is discussed. In the last section, recent contributions of responsive materials involving nucleolipids and their use as smart drug delivery systems are discussed. The supramolecular materials generated by nucleic acid based lipids open new challenges for biomedical applications, including the fields of medicinal chemistry, biosensors, biomaterials for tissue engineering, drug delivery, and the decontamination of nanoparticles.
Hybrid molecules combining nucleic acid structures with lipids have recently received increasing attention as a new class of supramolecular biomaterials. An overview of the latest studies on their chemical and biological properties is presented, including several biomedical applications ranging from medicinal chemistry to biomaterials. Some suggestions for developing these types of soft materials in the near future are also proposed.
We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to ...sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab–ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab–ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups.
This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0–2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab–ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab–ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab–ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment.
Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab–ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6–18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16–45) of 42 patients with nivolumab and 16 (39%; 24–55) of 41 patients with nivolumab–ipilimumab (odds ratio OR 0·63 95% CI 0·25–1·56). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20–70) of 16 patients with nivolumab and nine (50% 26–74) of 18 patients with nivolumab–ipilimumab (OR 0·78 95% CI 0·20–3·01). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33–67) of 36 patients with a VEGFR-TKI and 19 (51%; 34–68) of 37 patients with nivolumab–ipilimumab (OR 0·95 95% CI 0·38–2·37). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1–72) of five patients who received nivolumab–ipilimumab. The most common treatment-related grade 3–4 adverse events were hepatic failure and lipase increase (two 3% of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six 6% of 101 for both) with nivolumab–ipilimumab, and hypertension (six 15% of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab–ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab–ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib.
We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma.
Bristol Myers Squibb, ARTIC.
A family of new glycosyl-nucleoside lipids (GNLs) that were prepared using a convenient "double click" chemistry route is described. Physicochemical studies (surface tension measurements, gelation ...properties, and transmission electron microscopy) indicate that these amphiphiles spontaneously assemble into supramolecular structures including fibers, vesicles, hydrogels, and organogels. GNLs possess unique gelation properties both in water and chloroform. A very low minimum gelation concentration of 0.1% (w/w) was observed in the case of the amide-saturated derivative in water.
Hybrid lipid oligonucleotide conjugates are finding more and more biotechnological applications. This short critical review highlights their synthesis, supramolecular organization as well as their ...applications in the field of biotechnology (111 references).
In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell ...carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting.
In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment.
Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months IQR 13·4–36·3), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached 95% CI 35·6–not estimable vs 26·6 months 22·1–33·4; hazard ratio HR 0·66 95% CI 0·54–0·80, p<0·0001), progression-free survival (median 8·2 months 95% CI 6·9–10·0 vs 8·3 months 7·0–8·8; HR 0·77 95% CI 0·65–0·90, p=0·0014), and the proportion of patients achieving an objective response (178 42% of 425 vs 124 29% of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached 95% CI not estimable vs 37·9 months 32·2–not estimable; HR 0·71 95% CI 0·59–0·86, p=0·0003), progression-free survival (median 9·7 months 95% CI 8·1–11·1 vs 9·7 months 8·3–11·1; HR 0·85 95% CI 0·73–0·98, p=0·027), and the proportion of patients achieving an objective response (227 41% of 550 vs 186 34% of 546 p=0·015). In all treated patients, the most common grade 3–4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 10% of 547), increased amylase (31 6%), and increased alanine aminotransferase (28 5%), whereas in the sunitinib group they were hypertension (90 17% of 535), fatigue (51 10%), and palmar-plantar erythrodysaesthesia (49 9%). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related.
The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories.
Bristol-Myers Squibb and ONO Pharmaceutical.
There is a critical need for soft materials in the field of regenerative medicine and tissue engineering. However, designing injectable hydrogel scaffolds encompassing both adequate mechanical and ...biological properties remains a key challenge for in vivo applications. Here we use a bottom-up approach for synthesizing supramolecular gels to generate novel biomaterial candidates. We evaluated the low molecular weight gels candidates in vivo and identified one urea-containing molecule, compound 16, that avoid foreign body reactions in mice. The self-assembly of bolaamphiphiles creates a unique hydrogel supramolecular structures featuring fast gelation kinetics, high elastic moduli, thixotropic, and thermal reversibility properties. This soft material, which inhibits recognition by macrophages and fibrous deposition, exhibits long-term stability after in vivo injection.
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