Background: Despite the crucial role of integrin receptors in cancer pathogenesis and massive efforts towards establishing clinically relevant drugs, to the present no effective integrin antagonist for the treatment of malignant diseases has been introduced into the clinic.Context and purpose of the study: The purpose of the study was to examine the cellular effects and molecular mechanisms of a novel anti-integrin compound designated AV-398/38 and to compare it with cilengitide, one of the most advanced and best characterized αVβ3/αVβ5 integrin antagonists. AV-398/38 is a small molecule integrin antagonist that is currently in an early phase of pre-clinical evaluation. It was identified by virtual screening of chemical databases with the aim to detect novel integrin αVβ3 antagonist-like candidates. Based on preliminary in vitro data, the compound was recognized as a potential anti-neoplastic drug candidate, displaying high specificity and binding affinity in the nanomolar range towards the αVβ3 receptor, as well as showing potentially favorable drug-like properties.Results: Our studies revealed that its anti-neoplastic properties are most likely mediated by inhibition of integrin-mediated cell attachment to the extracellular matrix resulting in anoikis in a TP53 independent manner. Additionally, we observed inhibition of integrin-linked pathways involved in cell proliferation, survival and migration such as FAK, Akt, and MAPK as well as direct inhibitory effects on cell migration. We compared the effects of the compound with cilengitide, which is one of the bestcharacterized αVβ3 antagonists available. Main findings:The main finding was the observation, that AV-398/38 is capable of inducing cell death via induction of anoikis in a TP53 independent manner. Conclusions:Integrin αVβ3/αVβ5 inhibition leads to apoptotic cell death most likely triggered by a loss of adherence. Brief summary and potential implications:Our data indicate that compound AV-398/38 or structurally similar molecules may be promising candidates for preclinical development.
Background Patients with cancer are at high risk for severe courses of COVID-19. Based on (pre-)clinical data suggesting a potential protective effect due to the immunomodulating properties of azithromycin, we have initiated a prospective randomized trial. Methods This randomized, single-center, single-blinded, placebo-controlled phase 2 trial included adult patients with cancer undergoing systemic treatment. Patients were 1:1 randomized to oral azithromycin (1500 mg once weekly for 8 weeks) or placebo. The primary endpoint was the cumulative number of SARS-CoV-2 infections 12 weeks after treatment initiation. Results In total, 523 patients were screened, 68 patients were randomized, and 63 patients received at least one dose of the study drug. Due to low acceptance and a lack of SARS-CoV-2 infections in the study cohort, the study was prematurely closed. With no reported grade III–IV possibly treatment-related adverse events, azithromycin was generally well tolerated. Overall survival (OS) rates after 12 months were 83.5% and 70.3% in the azithromycin and placebo group, respectively (p = 0.37). Non-SARS-CoV-2 infections occurred in 4/32 (12.5%) in the azithromycin and 3/31 (9.7%) in the placebo group (p = 1). No emergence of azithromycin-resistant S. aureus strains could be observed. According to treatment group, longitudinal alterations in systemic inflammatory parameters were detected for neutrophil/lymphocyte and leukocyte/lymphocyte ratios. Conclusion Although efficacy could not be assessed due to premature closure and low incidence of SARS-CoV-2 infections, azithromycin was associated with a favorable side effect profile in patients with cancer. As other prophylactic treatments are limited, SARS-CoV-2 vaccination remains a high priority in oncological patients. ClinicalTrials.gov registration number and date (dd/mm/yyyy): NCT04369365, 30/04/2020.
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