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Viruses May 2018The Middle East respiratory syndrome-coronavirus (MERS-CoV), first identified in Saudi Arabia, is an emerging zoonotic pathogen that causes severe acute respiratory...
The Middle East respiratory syndrome-coronavirus (MERS-CoV), first identified in Saudi Arabia, is an emerging zoonotic pathogen that causes severe acute respiratory illness in humans with a high fatality rate. Since its emergence, MERS-CoV continues to spread to countries outside of the Arabian Peninsula and gives rise to sporadic human infections following the entry of infected individuals to other countries, which can precipitate outbreaks similar to the one that occurred in South Korea in 2015. Current therapeutics against MERS-CoV infection have primarily been adapted from previous drugs used for the treatment of severe acute respiratory syndrome. In search of new potential drug candidates, we screened a library composed of 2334 clinically approved drugs and pharmacologically active compounds. The drug saracatinib, a potent inhibitor of Src-family of tyrosine kinases (SFK), was identified as an inhibitor of MERS-CoV replication in vitro. Our results suggest that saracatinib potently inhibits MERS-CoV at the early stages of the viral life cycle in Huh-7 cells, possibly through the suppression of SFK signaling pathways. Furthermore, saracatinib exhibited a synergistic effect with gemcitabine, an anticancer drug with antiviral activity against several RNA viruses. These data indicate that saracatinib alone or in combination with gemcitabine can provide a new therapeutic option for the treatment of MERS-CoV infection.
Topics: Antiviral Agents; Benzodioxoles; Cell Line; Cross Infection; DNA Replication; Deoxycytidine; Drug Discovery; Enzyme Inhibitors; Humans; Middle East Respiratory Syndrome Coronavirus; Quinazolines; Small Molecule Libraries; Virus Replication; src-Family Kinases; Gemcitabine
PubMed: 29795047
DOI: 10.3390/v10060283 -
JAMA Psychiatry Nov 2021The COVID-19 pandemic has raised considerable concerns about increased risk for suicidal behavior among US military veterans, who already had elevated rates of suicide...
IMPORTANCE
The COVID-19 pandemic has raised considerable concerns about increased risk for suicidal behavior among US military veterans, who already had elevated rates of suicide before the pandemic.
OBJECTIVE
To examine longitudinal changes in suicidal behavior from before the COVID-19 pandemic to nearly 10 months into the pandemic and identify risk factors and COVID-related variables associated with new-onset suicide ideation (SI).
DESIGN, SETTING, AND PARTICIPANTS
This population-based prospective cohort study used data from the first and second wave of the National Health and Resilience in Veterans Study, conducted from November 18, 2019, to December 19, 2020. Median dates of data collection for the prepandemic and peripandemic assessments were November 21, 2019, and November 14, 2020, nearly 10 months after the start of the COVID-19 public health emergency in the US. A total of 3078 US military veterans aged 22 to 99 years were included in the study.
MAIN OUTCOMES AND MEASURES
Past-year SI and suicide attempts.
RESULTS
In this cohort study of 3078 US veterans (mean [SD] age, 63.2 [14.7] years; 91.6% men; 79.3% non-Hispanic White veterans, 10.3% non-Hispanic Black veterans, and 6.0% Hispanic veterans), 233 (7.8%) reported past-year SI, and 8 (0.3%) reported suicide attempts at the peripandemic assessment. Past-year SI decreased from 10.6% prepandemic (95% CI, 9.6%-11.8%) to 7.8% peripandemic (95% CI, 6.9%-8.8%). A total of 82 veterans (2.6%) developed new-onset SI over the follow-up period. After adjusting for sociodemographic and military characteristics, the strongest risk factors and COVID-19-related variables for new-onset SI were low social support (odds ratio [OR], 2.77; 95% CI, 1.46-5.28), suicide attempt history (OR, 6.31; 95% CI, 2.71-14.67), lifetime posttraumatic stress disorder and/or depression (OR, 2.25; 95% CI, 1.16-4.35), past-year alcohol use disorder severity (OR, 1.06; 95% CI, 1.01-1.12), COVID-19 infection (OR, 2.41; 95% CI, 1.41-5.01), and worsening of social relationships during the pandemic (OR, 1.47; 95% CI, 1.16-1.88).
CONCLUSIONS AND RELEVANCE
The results of this cohort study suggest that despite grim forecasts that the COVID-19 pandemic would exacerbate suicidality among US military veterans, the rate of SI decreased at the population level nearly 10 months into the pandemic. Veterans who were infected with COVID-19 were more than twice as likely to report SI, which suggests the need for future research to examine the potential link between COVID-19 infection and suicidal behavior.
Topics: Adult; Aged; COVID-19; Female; Humans; Longitudinal Studies; Male; Middle Aged; Prevalence; Risk Factors; Suicidal Ideation; United States; Veterans
PubMed: 34431973
DOI: 10.1001/jamapsychiatry.2021.2332 -
Sarcoma 2020Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. The Src pathway has been implicated in...
PURPOSE
Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. The Src pathway has been implicated in the metastatic behavior of osteosarcoma; about 95% of samples examined express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor that was evaluated in adults in Phase 1 studies. The primary goal of this study was to determine if treatment with saracatinib could increase progression-free survival (PFS) for patients who have undergone complete resection of osteosarcoma lung metastases in a double-blinded, placebo-controlled trial. . Subjects with recurrent osteosarcoma localized to lung and who had complete surgical removal of all lung nodules were randomized within six weeks after complete surgical resection. Saracatinib, or placebo, was administered at a dose of 175 mg orally, once daily, for up to thirteen 28-day cycles.
RESULTS
Thirty-seven subjects were included in the analyses; 18 subjects were randomized to receive saracatinib and 19 to receive placebo. Intent-to-treat analysis demonstrated a median PFS of 19.4 months in the saracatinib treatment group and 8.6 months in the placebo treatment group (=0.47). Median OS was not reached in either arm.
CONCLUSIONS
Although saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this double-blinded, placebo-controlled trial on OS, and Src inhibition alone may not be sufficient to suppress metastatic progression in osteosarcoma. There is a suggestion of potential clinical benefit as evidenced by longer PFS in patients randomized to saracatinib based on limited numbers of patients treated.
PubMed: 32398945
DOI: 10.1155/2020/7935475 -
Neuropsychopharmacology : Official... Mar 2022Altered striatal regulation of the GluN2B subunit of N-methyl-D-aspartate (NMDA) glutamate receptors by the Fyn/Src family of protein tyrosine kinases has been... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of the Fyn kinase inhibitor saracatinib on ventral striatal activity during performance of an fMRI monetary incentive delay task in individuals family history positive or negative for alcohol use disorder. A pilot randomised trial.
Altered striatal regulation of the GluN2B subunit of N-methyl-D-aspartate (NMDA) glutamate receptors by the Fyn/Src family of protein tyrosine kinases has been implicated in animal alcohol consumption. Previously, we have described differences between individuals positive (FHP) and negative (FHN) for familial alcohol use disorder (AUD) in the ventral striatal (VS) activation associated with monetary incentive delay task (MIDT) performance during functional magnetic resonance imaging (fMRI). Here, we used AZD0530 (saracatinib), a centrally active Fyn/Src inhibitor to probe the role of Fyn/Src regulation of NMDA receptors (NMDAR) in VS activation differences between FHP and FHN individuals during fMRI MIDT performance. We studied 21 FHN and 22 FHP individuals, all without AUD. In two sessions, spaced 1 week apart, we administered 125 mg of saracatinib or placebo in a double-blind manner, prior to measuring VS signal during fMRI MIDT performance. MIDT comprises reward prospect, anticipation, and outcome phases. During the initial (prospect of reward) task phase, there was a significant group-by-condition interaction such that, relative to placebo, saracatinib reduced VS BOLD signal in FHP and increased it in FHN individuals. This study provides the first human evidence that elevated signaling in striatal protein kinase A-dependent pathways may contribute to familial AUD risk via amplifying the neural response to the prospect of reward. As Fyn kinase is responsible for NMDAR upregulation, these data are consistent with previous evidence for upregulated NMDAR function within reward circuitry in AUD risk. These findings also suggest a possible therapeutic role for Src/Fyn kinase inhibitors in AUD risk.
Topics: Alcohol Drinking; Alcoholism; Benzodioxoles; Humans; Magnetic Resonance Imaging; Motivation; Pilot Projects; Quinazolines; Reward
PubMed: 34475522
DOI: 10.1038/s41386-021-01157-5 -
IScience Sep 2021Resistance to current therapies is common for pancreatic cancer and hence novel treatment options are urgently needed. In this work, we developed and validated a...
Resistance to current therapies is common for pancreatic cancer and hence novel treatment options are urgently needed. In this work, we developed and validated a computational method to select synergistic compound combinations based on transcriptomic profiles from both the disease and compound side, combined with a pathway scoring system, which was then validated prospectively by testing 30 compounds (and their combinations) on PANC-1 cells. Some compounds selected as single agents showed lower GI50 values than the standard of care, gemcitabine. Compounds suggested as combination agents with standard therapy gemcitabine based on the best performing scoring system showed on average 2.82-5.18 times higher synergies compared to compounds that were predicted to be active as single agents. Examples of highly synergistic in vitro validated compound pairs include gemcitabine combined with Entinostat, thioridazine, loperamide, scriptaid and Saracatinib. Hence, the computational approach presented here was able to identify synergistic compound combinations against pancreatic cancer cells.
PubMed: 34585118
DOI: 10.1016/j.isci.2021.103080 -
International Journal of Molecular... Jun 2024Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with few effective treatments. EGFR alterations, including expression of the truncated...
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with few effective treatments. EGFR alterations, including expression of the truncated variant EGFRvIII, are among the most frequent genomic changes in these tumors. EGFRvIII is known to preferentially signal through STAT5 for oncogenic activation in GBM, yet targeting EGFRvIII has yielded limited clinical success to date. In this study, we employed patient-derived xenograft (PDX) models expressing EGFRvIII to determine the key points of therapeutic vulnerability within the EGFRvIII-STAT5 signaling axis in GBM. Our findings reveal that exogenous expression of paralogs STAT5A and STAT5B augments cell proliferation and that inhibition of STAT5 phosphorylation in vivo improves overall survival in combination with temozolomide (TMZ). STAT5 phosphorylation is independent of JAK1 and JAK2 signaling, instead requiring Src family kinase (SFK) activity. Saracatinib, an SFK inhibitor, attenuates phosphorylation of STAT5 and preferentially sensitizes EGFRvIII+ GBM cells to undergo apoptotic cell death relative to wild-type EGFR. Constitutively active STAT5A or STAT5B mitigates saracatinib sensitivity in EGFRvIII+ cells. In vivo, saracatinib treatment decreased survival in mice bearing EGFR WT tumors compared to the control, yet in EGFRvIII+ tumors, treatment with saracatinib in combination with TMZ preferentially improves survival.
Topics: STAT5 Transcription Factor; Glioblastoma; Humans; Animals; Quinazolines; Benzodioxoles; Mice; ErbB Receptors; Phosphorylation; Cell Line, Tumor; Temozolomide; Cell Proliferation; Xenograft Model Antitumor Assays; Signal Transduction; Brain Neoplasms; Apoptosis; src-Family Kinases; Tumor Suppressor Proteins
PubMed: 38892466
DOI: 10.3390/ijms25116279 -
Cell Communication and Signaling : CCS Jan 2024Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that play an important role in cancer progression. Although the mechanism by...
BACKGROUND
Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that play an important role in cancer progression. Although the mechanism by which CAFs promote tumorigenesis has been well investigated, the underlying mechanism of CAFs activation by neighboring cancer cells remains elusive. In this study, we aim to investigate the signaling pathways involved in CAFs activation by gastric cancer cells (GC) and to provide insights into the therapeutic targeting of CAFs for overcoming GC.
METHODS
Alteration of receptor tyrosine kinase (RTK) activity in CAFs was analyzed using phospho-RTK array. The expression of CAFs effector genes was determined by RT-qPCR or ELISA. The migration and invasion of GC cells co-cultured with CAFs were examined by transwell migration/invasion assay.
RESULTS
We found that conditioned media (CM) from GC cells could activate multiple receptor tyrosine kinase signaling pathways, including ERK, AKT, and STAT3. Phospho-RTK array analysis showed that CM from GC cells activated PDGFR tyrosine phosphorylation, but only AKT activation was PDGFR-dependent. Furthermore, we found that connective tissue growth factor (CTGF), a member of the CCN family, was the most pronouncedly induced CAFs effector gene by GC cells. Knockdown of CTGF impaired the ability of CAFs to promote GC cell migration and invasion. Although the PDGFR-AKT pathway was pronouncedly activated in CAFs stimulated by GC cells, its pharmacological inhibition affected neither CTGF induction nor CAFs-induced GC cell migration. Unexpectedly, the knockdown of SRC and SRC-family kinase inhibitors, dasatinib and saracatinib, significantly impaired CTGF induction in activated CAFs and the migration of GC cells co-cultured with CAFs. SRC inhibitors restored the reduced expression of epithelial markers, E-cadherin and Zonula Occludens-1 (ZO-1), in GC cells co-cultured with CAFs, as well as CAFs-induced aggregate formation in a 3D tumor spheroid model.
CONCLUSIONS
This study provides a characterization of the signaling pathways and effector genes involved in CAFs activation, and strategies that could effectively inhibit it in the context of GC. Video Abstract.
Topics: Humans; Cancer-Associated Fibroblasts; Cell Line, Tumor; Cell Movement; Cell Proliferation; Connective Tissue Growth Factor; Fibroblasts; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Stomach Neoplasms; Tumor Microenvironment
PubMed: 38167009
DOI: 10.1186/s12964-023-01396-7 -
Clinical Cancer Research : An Official... Oct 2018Rational targeted therapies are needed for treatment of ovarian cancers. Signaling kinases Src and MAPK are activated in high-grade serous ovarian cancer (HGSOC). Here,...
Rational targeted therapies are needed for treatment of ovarian cancers. Signaling kinases Src and MAPK are activated in high-grade serous ovarian cancer (HGSOC). Here, we tested the frequency of activation of both kinases in HGSOC and the therapeutic potential of dual kinase inhibition. MEK and Src activation was assayed in primary HGSOC from The Cancer Genome Atlas (TGGA). Effects of dual kinase inhibition were assayed on cell-cycle, apoptosis, gene, and proteomic analysis; cancer stem cells; and xenografts. Both Src and MAPK are coactivated in 31% of HGSOC, and this associates with worse overall survival on multivariate analysis. Frequent dual kinase activation in HGSOC led us to assay the efficacy of combined Src and MEK inhibition. Treatment of established lines and primary ovarian cancer cultures with Src and MEK inhibitors saracatinib and selumetinib, respectively, showed target kinase inhibition and synergistic induction of apoptosis and cell-cycle arrest and tumor inhibition in xenografts. Gene expression and proteomic analysis confirmed cell-cycle inhibition and autophagy. Dual therapy also potently inhibited tumor-initiating cells. Src and MAPK were both activated in tumor-initiating populations. Combination treatment followed by drug washout decreased sphere formation and ALDH1 cells. tumors dissociated after dual therapy showed a marked decrease in ALDH1 staining, sphere formation, and loss of tumor-initiating cells upon serial xenografting. Selumetinib added to saracatinib overcomes EGFR/HER2/ERBB2-mediated bypass activation of MEK/MAPK observed with saracatinib alone and targets tumor-initiating ovarian cancer populations, supporting further evaluation of combined Src-MEK inhibition in clinical trials. .
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzimidazoles; Benzodioxoles; Cell Line, Tumor; Cell Proliferation; Disease-Free Survival; Drug Resistance, Neoplasm; Estrogen Receptor alpha; Female; Humans; MAP Kinase Kinase 1; Mice; Middle Aged; Neoplastic Stem Cells; Ovarian Neoplasms; Protein Kinase Inhibitors; Proteomics; Quinazolines; Xenograft Model Antitumor Assays; src-Family Kinases
PubMed: 29959144
DOI: 10.1158/1078-0432.CCR-17-3697 -
Pharmaceuticals (Basel, Switzerland) Sep 2021Osteosarcoma (OS) is an aggressive mesenchymal cell tumor that carries a poor long-term prognosis. Despite definitive surgery for the primary tumor and adjuvant...
Osteosarcoma (OS) is an aggressive mesenchymal cell tumor that carries a poor long-term prognosis. Despite definitive surgery for the primary tumor and adjuvant chemotherapy, pulmonary metastasis is common and is the primary cause of morbidity. To improve outcomes for patients, we have developed and optimized a phenotypic screen for drugs that may target OS disseminated tumor cells (DTCs) and inhibit their metastatic outbreak rather than merely screening for cytotoxic activity against proliferating cells, as is commonly conducted in conventional drug discovery approaches. We report on the validation of a previously described 3D reconstituted basement membrane extract (3D BME) model system for tumor dormancy and metastatic outgrowth adapted to clonal pairs of high and low metastatic OS cells. A post-hoc validation of the assay was possible by comparing the activity of a drug in our assay with early evidence of activity in human OS clinical trials (regorafenib and saracatinib). In this validation, we found concordance between our assay and human clinical trial experience We then explored an approved veterinary small molecule inhibitor of Janus kinase-1 (oclacitinib) as a potential drug candidate to take advantage of the high prevalence of OS in pet dogs and its translational value to humans. Despite the biological rationale, we found no evidence to support the use of oclacitinib as an antimetastatic agent in OS. The findings support our 3D BME assay as a highly efficient method to examine drugs for activity in targeting OS DTCs.
PubMed: 34681195
DOI: 10.3390/ph14100971 -
Journal of Bone Oncology Dec 2019Pain is a major symptom of bone metastases from advanced cancer and represents a clinical challenge to treat effectively. Basic neurobiology in preclinical animal models...
Pain is a major symptom of bone metastases from advanced cancer and represents a clinical challenge to treat effectively. Basic neurobiology in preclinical animal models implicates enhanced sensory processing in the central nervous system, acting through -methyl-D-aspartate (NMDA) glutamate receptors, as an important mechanism underpinning persistent pain. The non-receptor tyrosine kinase Src is thought to act as a hub for regulating NMDA receptor activity and the orally available Src inhibitor saracatinib has shown promise as a potential analgesic in recent animal studies. Here we tested the efficacy of saracatinib as a novel analgesic in an exploratory phase II randomized controlled trial on cancer patients with painful bone metastases. Twelve patients completed the study, with 6 receiving saracatinib 125 mg/day for 28 days and 6 receiving placebo. Pharmacokinetic measurements confirmed appropriate plasma levels of drug in the saracatinib-treated group and Src inhibition was achieved clinically by a significant reduction in the bone resorption biomarker serum cross-linked C-terminal telopeptide of type I collagen. Differences between the saracatinib and placebo groups self-reported pain scores, measured using the short form of the Brief Pain Inventory, were not clinically significant after 4 weeks of treatment. There was also no change in consumption of maintenance analgesia in the saracatinib-treated group and no improvement in Quality-of-Life scores. The data were insufficient to demonstrate saracatinib has efficacy as analgesic, although it may have a role as an anti-bone resorptive agent.
PubMed: 31667062
DOI: 10.1016/j.jbo.2019.100261