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International Journal of Molecular... Apr 2024Saracatinib (AZD0530) is a dual Src/Abl inhibitor initially developed by AstraZeneca for cancer treatment; however, data from 2006 to 2024 reveal that this drug has been... (Review)
Review
Saracatinib (AZD0530) is a dual Src/Abl inhibitor initially developed by AstraZeneca for cancer treatment; however, data from 2006 to 2024 reveal that this drug has been tested not only for cancer treatment, but also for the treatment of other diseases. Despite the promising pre-clinical results and the tolerability shown in phase I trials, where a maximum tolerated dose of 175 mg was defined, phase II clinical data demonstrated a low therapeutic action against several cancers and an elevated rate of adverse effects. Recently, pre-clinical research aimed at reducing the toxic effects and enhancing the therapeutic performance of saracatinib using nanoparticles and different pharmacological combinations has shown promising results. Concomitantly, saracatinib was repurposed to treat Alzheimer's disease, targeting Fyn. It showed great clinical results and required a lower daily dose than that defined for cancer treatment, 125 mg and 175 mg, respectively. In addition to Alzheimer's disease, this Src inhibitor has also been studied in relation to other health conditions such as pulmonary and liver fibrosis and even for analgesic and anti-allergic functions. Although saracatinib is still not approved by the Food and Drug Administration (FDA), the large number of alternative uses for saracatinib and the elevated number of pre-clinical and clinical trials performed suggest the huge potential of this drug for the treatment of different kinds of diseases.
Topics: Humans; Drug Repositioning; Quinazolines; Benzodioxoles; Animals; Protein Kinase Inhibitors; Alzheimer Disease; src-Family Kinases; Neoplasms; Antineoplastic Agents
PubMed: 38674150
DOI: 10.3390/ijms25084565 -
Biological Psychiatry Feb 2018The past decade has brought tremendous progress in unraveling the pathophysiology of Alzheimer's disease (AD). While increasingly sophisticated immunotherapy targeting... (Review)
Review
The past decade has brought tremendous progress in unraveling the pathophysiology of Alzheimer's disease (AD). While increasingly sophisticated immunotherapy targeting soluble and aggregated brain amyloid-beta (Aβ) continues to dominate clinical research in AD, a deeper understanding of Aβ physiology has led to the recognition of distinct neuronal signaling pathways linking Aβ to synaptotoxicity and neurodegeneration and to new targets for therapeutic intervention. Identifying specific signaling pathways involving Aβ has allowed for the development of more precise therapeutic interventions targeting the most relevant molecular mechanisms leading to AD. In this review, I highlight the discovery of cellular prion protein as a high-affinity receptor for Aβ oligomers, and the downstream signaling pathway elucidated to date, converging on nonreceptor tyrosine kinase Fyn. I discuss preclinical studies targeting Fyn as a therapeutic intervention in AD and our recent experience with the safety, tolerability, and cerebrospinal fluid penetration of the Src family kinase inhibitor saracatinib in patients with AD. Fyn is an attractive target for AD therapeutics, not only based on its activation by Aβ via cellular prion protein but also due to its known interaction with tau, uniquely linking the two key pathologies in AD. Fyn is also a challenging target, with broad expression throughout the body and significant homology with other members of the Src family kinases, which may lead to unintended off-target effects. A phase 2a proof-of-concept clinical trial in patients with AD is currently under way, providing critical first data on the potential effectiveness of targeting Fyn in AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzodioxoles; Enzyme Inhibitors; Humans; Prion Proteins; Proto-Oncogene Proteins c-fyn; Quinazolines
PubMed: 28709498
DOI: 10.1016/j.biopsych.2017.06.004 -
Frontiers in Cellular Neuroscience 2021Acute organophosphate (OP) toxicity poses a significant threat to both military and civilian personnel as it can lead to a variety of cholinergic symptoms including the...
Differential Impact of Severity and Duration of , Medical Countermeasures, and a Disease-Modifier, Saracatinib, on Brain Regions in the Rat Diisopropylfluorophosphate Model.
Acute organophosphate (OP) toxicity poses a significant threat to both military and civilian personnel as it can lead to a variety of cholinergic symptoms including the development of (SE). Depending on its severity, SE can lead to a spectrum of neurological changes including neuroinflammation and neurodegeneration. In this study, we determined the impact of SE severity and duration on disease promoting parameters such as gliosis and neurodegeneration and the efficacy of a disease modifier, saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor. Animals were exposed to 4 mg/kg diisopropylfluorophosphate (DFP, s.c.) followed by medical countermeasures. We had five experimental groups: controls (no DFP), animals with no continuous convulsive seizures (CS), animals with ∼20-min continuous CS, 31-60-min continuous CS, and > 60-min continuous CS. These groups were then assessed for astrogliosis, microgliosis, and neurodegeneration 8 days after DFP exposure. The 31-60-min and > 60-min groups, but not ∼20-min group, had significantly upregulated gliosis and neurodegeneration in the hippocampus compared to controls. In the piriform cortex and amygdala, however, all three continuous CS groups had significant upregulation in both gliosis and neurodegeneration. In a separate cohort of animals that had ∼20 and > 60-min of continuous CS, we administered saracatinib for 7 days beginning three hours after DFP. There was bodyweight loss and mortality irrespective of the initial SE severity and duration. However, in survived animals, saracatinib prevented spontaneous recurrent seizures (SRS) during the first week in both severity groups. In the ∼20-min CS group, compared to the vehicle, saracatinib significantly reduced neurodegeneration in the piriform cortex and amygdala. There were no significant differences in the measured parameters between the naïve control and saracatinib on its own (without DFP) groups. Overall, this study demonstrates the differential effects of the initial SE severity and duration on the localization of gliosis and neurodegeneration. We have also demonstrated the disease-modifying potential of saracatinib. However, its' dosing regimen should be optimized based on initial severity and duration of CS during SE to maximize therapeutic effects and minimize toxicity in the DFP model as well as in other OP models such as soman.
PubMed: 34720886
DOI: 10.3389/fncel.2021.772868 -
Frontiers in Oncology 2023Prostate cancer (PCa) remains the most diagnosed non-skin cancer amongst the American male population. Treatment for localized prostate cancer consists of androgen...
Prostate cancer (PCa) remains the most diagnosed non-skin cancer amongst the American male population. Treatment for localized prostate cancer consists of androgen deprivation therapies (ADTs), which typically inhibit androgen production and the androgen receptor (AR). Though initially effective, a subset of patients will develop resistance to ADTs and the tumors will transition to castration-resistant prostate cancer (CRPC). Second generation hormonal therapies such as abiraterone acetate and enzalutamide are typically given to men with CRPC. However, these treatments are not curative and typically prolong survival only by a few months. Several resistance mechanisms contribute to this lack of efficacy such as the emergence of AR mutations, AR amplification, lineage plasticity, AR splice variants (AR-Vs) and increased kinase signaling. Having identified SRC kinase as a key tyrosine kinase enriched in CRPC patient tumors from our previous work, we evaluated whether inhibition of SRC kinase synergizes with enzalutamide or chemotherapy in several prostate cancer cell lines expressing variable AR isoforms. We observed robust synergy between the SRC kinase inhibitor, saracatinib, and enzalutamide, in the AR-FL+/AR-V+ CRPC cell lines, LNCaP95 and 22Rv1. We also observed that saracatinib significantly decreases AR Y phosphorylation, a key SRC kinase substrate residue, on AR-FL and AR-Vs, along with the AR regulome, supporting key mechanisms of synergy with enzalutamide. Lastly, we also found that the saracatinib-enzalutamide combination reduced DNA replication compared to the saracatinib-docetaxel combination, resulting in marked increased apoptosis. By elucidating this combination strategy, we provide pre-clinical data that suggests combining SRC kinase inhibitors with enzalutamide in select patients that express both AR-FL and AR-Vs.
PubMed: 37456235
DOI: 10.3389/fonc.2023.1210487 -
Neuropsychopharmacology : Official... Jul 2022This study tested the efficacy of repeated intravenous ketamine doses to reduce symptoms of posttraumatic stress disorder (PTSD). Veterans and service members with PTSD... (Randomized Controlled Trial)
Randomized Controlled Trial
Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial.
This study tested the efficacy of repeated intravenous ketamine doses to reduce symptoms of posttraumatic stress disorder (PTSD). Veterans and service members with PTSD (n = 158) who failed previous antidepressant treatment were randomized to 8 infusions administered twice weekly of intravenous placebo (n = 54), low dose (0.2 mg/kg; n = 53) or standard dose (0.5 mg/kg; n = 51) ketamine. Participants were assessed at baseline, during treatment, and for 4 weeks after their last infusion. Primary analyses used mixed effects models. The primary outcome measure was the self-report PTSD Checklist for DSM-5 (PCL-5), and secondary outcome measures were the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and the Montgomery Åsberg Depression Rating Scale (MADRS). There were no significant group-by-time interactions for PTSD symptoms measured by the PCL-5 or CAPS-5. The standard ketamine dose ameliorated depression measured by the MADRS significantly more than placebo. Ketamine produced dose-related dissociative and psychotomimetic effects, which returned to baseline within 2 h and were less pronounced with repeated administration. There was no evidence of differential treatment discontinuation by ketamine dose, consistent with good tolerability. This clinical trial failed to find a significant dose-related effect of ketamine on PTSD symptoms. Secondary analyses suggested that the standard dose exerted rapid antidepressant effects. Further studies are needed to determine the role of ketamine in PTSD treatment. ClinicalTrials.gov identifier: NCT02655692.
Topics: Antidepressive Agents; Double-Blind Method; Humans; Ketamine; Military Personnel; Stress Disorders, Post-Traumatic; Treatment Outcome; Veterans
PubMed: 35046508
DOI: 10.1038/s41386-022-01266-9 -
Journal of Hematology & Oncology Dec 2019Src, an oncoprotein that drives progression of head and neck squamous cell carcinoma (HNSCC), is commonly hyperactivated in this disease. Unfortunately, the clinical...
Simultaneously inactivating Src and AKT by saracatinib/capivasertib co-delivery nanoparticles to improve the efficacy of anti-Src therapy in head and neck squamous cell carcinoma.
BACKGROUND
Src, an oncoprotein that drives progression of head and neck squamous cell carcinoma (HNSCC), is commonly hyperactivated in this disease. Unfortunately, the clinical benefit of targeting Src is significantly dampened in HNSCC patients, because the cytotoxic effects of anti-Src therapy and tumor resistance to it are less predictable. Thus, understanding the mechanism of tumor resistance to Src inhibition and seeking a way to overcome it are warranted.
METHODS
Dual drug-loaded nanoparticles (NPs) were developed to co-deliver Src inhibitor saracatinib (AZD0530) and AKT inhibitor capivasertib (AZD5363) into the same population of tumor cells. An orthotopic tongue tumor model was generated to evaluate the in vivo therapeutic effects. Cell growth was determined by CellTiter-Glo® Luminescent Cell Viability Kit, colony formation, and 3D culture, and tumor growth was determined by bioluminescence and tumor size. The molecular changes induced by the treatments were assessed by Western blotting and immunohistochemistry.
RESULTS
Capivasertib inactivated the AKT-S6 signaling and re-sensitized saracatinib-resistant HNSCC cells to saracatinib. Combination of capivasertib with saracatinib suppressed HNSCC growth more efficiently than either drug alone. Cathepsin B-sensitive NPs for co-delivering saracatinib and capivasertib significantly improved the efficacy of tumor repression without increasing side effects, which were due to highly specific tumor-targeting drug delivery system and synergistic anticancer effects by co-inactivation of AKT and Src in HNSCC cells.
CONCLUSIONS
Addition of AKT blockade improves anti-HNSCC efficacy of anti-Src therapy, and co-delivery of capivasertib and saracatinib by tumor-targeting NPs has the potential to achieve better treatment outcomes than the free drug combination.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzodioxoles; Biomarkers, Tumor; Cell Movement; Cell Proliferation; Drug Delivery Systems; Drug Resistance, Neoplasm; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Male; Mice; Mice, Inbred NOD; Mice, SCID; Nanoparticles; Neoplasm Invasiveness; Proto-Oncogene Proteins c-akt; Pyrimidines; Pyrroles; Quinazolines; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; src-Family Kinases
PubMed: 31805962
DOI: 10.1186/s13045-019-0827-1 -
Biomedicines Oct 2023Thymic epithelial tumors (TET) are rare neoplasms of the anterior mediastinum. Surgery is the mainstay treatment for resectable TET, whereas systemic treatments are... (Review)
Review
BACKGROUND
Thymic epithelial tumors (TET) are rare neoplasms of the anterior mediastinum. Surgery is the mainstay treatment for resectable TET, whereas systemic treatments are reserved for unresectable and metastatic tumors. The development of new treatments, such as immune checkpoint inhibitors (ICI) and targeted therapies, with promising results in other types of solid tumors, has led to the investigation of their potential efficacy in TET. The study of tumor microenvironments (TME) is another field of investigation that has gained the interest of researchers. Taking into account the complex structure of the thymus and its function in the development of immunity, researchers have focused on TME elements that could predict ICI efficacy.
MATERIALS AND METHODS
The primary objective of this systematic review was to investigate the efficacy of ICI in TET. Secondary objectives included the toxicity of ICI, the efficacy of targeted therapies in TET, and the evaluation of the elements of TME that may be predictive factors of ICI efficacy. A literature search was conducted in February 2023 using the Ovid Medline and SciVerse Scopus databases.
RESULTS
2944 abstracts were retrieved, of which 31 were retained for the systematic review. Five phase II and one retrospective study assessed ICI efficacy. The overall response rate (ORR) varied from 0% to 34%. Median progression-free survival (PFS) ranged from 3.8 to 8.6 months, being lower in thymic carcinoma (TC) (3.8-4.2 months). Median overall survival (OS) ranged from 14.1 to 35.4 months. Treatment-related adverse events occurred in 6.6% to 27.3% of patients. Sixteen studies assessed targeted therapies. The most active molecule was lenvatinib, with 38% ORR in patients with TC while no activity was detected for imatinib, erlotinib plus bevacizumab, and saracatinib. Ten studies assessed TME elements that could predict ICI efficacy. Four studies focused on the tumor-infiltrating immune cells suggesting improved outcomes in patients with TC and high tumor-infiltrating lymphocyte densities. Another study showed that CD8+, CD20+, and CD204+ tumor-infiltrating immune cells in cancer stroma might be prognostic biomarkers in TC. Another study identified the immune-related long non-coding RNAs as a predictor of response to ICI. Tumor mutational burden was identified as a predictive factor of ICI efficacy in one study.
CONCLUSIONS
Despite study heterogeneity, this review shows that ICI could be a therapeutic option for selected patients with TET that are not amenable to curative radical treatment after first-line chemotherapy.
PubMed: 37893096
DOI: 10.3390/biomedicines11102722 -
Frontiers in Microbiomes 2022Organophosphate nerve agents (OPNAs) act as irreversible inhibitors of acetylcholinesterase and can lead to cholinergic crisis including salivation, lacrimation,...
Organophosphate nerve agents (OPNAs) act as irreversible inhibitors of acetylcholinesterase and can lead to cholinergic crisis including salivation, lacrimation, urination, defecation, gastrointestinal distress, respiratory distress, and seizures. Although the OPNAs have been studied in the past few decades, little is known about the impact on the gut microbiome which has become of increasing interest across fields. In this study, we challenged animals with the OPNA, diisopropylfluorophosphate (DFP, 4mg/kg, s.c.) followed immediately by 2mg/kg atropine sulfate (i.m.) and 25mg/kg 2-pralidoxime (i.m.) and 30 minutes later by 3mg/kg midazolam (i.m.). One hour after midazolam, animals were treated with a dosing regimen of saracatinib (SAR, 20mg/kg, oral), a src family kinase inhibitor, to mitigate DFP-induced neurotoxicity. We collected fecal samples 48 hours, 7 days, and 5 weeks post DFP intoxication. 16S rRNA genes (V4) were amplified to identify the bacterial composition. At 48 hours, a significant increase in the abundance of and decrease in the abundance of were observed in DFP treated animals. At 7 days there was a significant reduction in and , but a significant increase in in the DFP groups compared to controls. The taxonomic changes at 5 weeks were negligible. There was no impact of SAR administration on microbial composition. There was a significant DFP-induced reduction in alpha diversity at 48 hours but not at 7 days and 5 weeks. There appeared to be an impact of DFP on beta diversity at 48 hours and 7 days but not at 5 weeks. In conclusion, acute doses of DFP lead to short-term gut dysbiosis and SAR had no effect. Understanding the role of gut dysbiosis in long-term toxicity may reveal therapeutic targets.
PubMed: 37304619
DOI: 10.3389/frmbi.2022.1006078 -
JCI Insight Apr 2021Currently, no effective therapies exist for fibrodysplasia ossificans progressiva (FOP), a rare congenital syndrome in which heterotopic bone is formed in soft tissues...
Currently, no effective therapies exist for fibrodysplasia ossificans progressiva (FOP), a rare congenital syndrome in which heterotopic bone is formed in soft tissues owing to dysregulated activity of the bone morphogenetic protein (BMP) receptor kinase ALK2 (also known as ACVR1). From a screen of known biologically active compounds, we identified saracatinib as a potent ALK2 kinase inhibitor. In enzymatic and cell-based assays, saracatinib preferentially inhibited ALK2, compared with other receptors of the BMP/TGF-β signaling pathway, and induced dorsalization in zebrafish embryos consistent with BMP antagonism. We further tested the efficacy of saracatinib using an inducible ACVR1Q207D-transgenic mouse line, which provides a model of heterotopic ossification (HO), as well as an inducible ACVR1R206H-knockin mouse, which serves as a genetically and physiologically faithful FOP model. In both models, saracatinib was well tolerated and potently inhibited the development of HO, even when administered transiently following soft tissue injury. Together, these data suggest that saracatinib is an efficacious clinical candidate for repositioning in FOP treatment, offering an accelerated path to clinical proof-of-efficacy studies and potentially significant benefits to individuals with this devastating condition.
Topics: Activin Receptors, Type I; Animals; Benzodioxoles; Bone Morphogenetic Proteins; Drug Evaluation, Preclinical; Gene Knock-In Techniques; Mice; Mice, Transgenic; Muscles; Myositis Ossificans; Ossification, Heterotopic; Quinazolines; Zebrafish
PubMed: 33705358
DOI: 10.1172/jci.insight.95042 -
Journal of Hematology & Oncology Jun 2018Inhibition of metastasis of head and neck squamous cell carcinoma (HNSCC) is one of the most important challenges in cancer treatment. Src, a non-receptor tyrosine...
BACKGROUND
Inhibition of metastasis of head and neck squamous cell carcinoma (HNSCC) is one of the most important challenges in cancer treatment. Src, a non-receptor tyrosine kinase, has been implicated as a key promoter in tumor progression and metastasis of HNSCC. However, Src therapy for HNSCC is limited by lack of efficient in vivo delivery and underlying mechanisms remain elusive.
METHODS
Src knockdown cells were achieved by lentiviral-mediated interference. Cell migration and invasion were examined by wound healing and Transwell assays. Protein levels were determined by Western blot and/or immunohistochemistry. The Src inhibitor saracatinib was loaded into self-assembling nanoparticles by the solvent evaporation method. An experimental metastasis mouse model was generated to investigate the drug efficacy in metastasis.
RESULTS
Blockade of Src kinase activity by saracatinib effectively suppressed invasion and metastasis of HNSCC. Mechanistic assessment of the drug effects in HNSCC cells showed that saracatinib induced suppression of Src-dependent invasion/metastasis through downregulating the expression levels of Vimentin and Snail proteins. In tests in mice, saracatinib loaded into the novel multifunctional nanoparticles exhibited superior effects on suppression of HNSCC metastasis compared with the free drug, which is mainly attributed to highly specific and efficient tumor-targeted drug delivery system.
CONCLUSIONS
These findings and advances are of great importance to the development of Src-targeted nanomedicine as a more effective therapy for metastatic HNSCC.
Topics: Animals; Antineoplastic Agents; Benzodioxoles; Disease Models, Animal; Drug Carriers; Enzyme Inhibitors; Head and Neck Neoplasms; Mice; Nanomedicine; Nanoparticles; Neoplasm Metastasis; Quinazolines; Snail Family Transcription Factors; Vimentin; src-Family Kinases
PubMed: 29925404
DOI: 10.1186/s13045-018-0623-3