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Pharmaceutics Apr 2021Since coronavirus disease 2019 (COVID-19) is a serious new worldwide public health crisis with significant morbidity and mortality, effective therapeutic treatments are...
Since coronavirus disease 2019 (COVID-19) is a serious new worldwide public health crisis with significant morbidity and mortality, effective therapeutic treatments are urgently needed. Drug repurposing is an efficient and cost-effective strategy with minimum risk for identifying novel potential treatment options by repositioning therapies that were previously approved for other clinical outcomes. Here, we used an integrated network-based pharmacologic and transcriptomic approach to screen drug candidates novel for COVID-19 treatment. Network-based proximity scores were calculated to identify the drug-disease pharmacological effect between drug-target relationship modules and COVID-19 related genes. Gene set enrichment analysis (GSEA) was then performed to determine whether drug candidates influence the expression of COVID-19 related genes and examine the sensitivity of the repurposing drug treatment to peripheral immune cell types. Moreover, we used the complementary exposure model to recommend potential synergistic drug combinations. We identified 18 individual drug candidates including nicardipine, orantinib, tipifarnib and promethazine which have not previously been proposed as possible treatments for COVID-19. Additionally, 30 synergistic drug pairs were ultimately recommended including fostamatinib plus tretinoin and orantinib plus valproic acid. Differential expression genes of most repurposing drugs were enriched significantly in B cells. The findings may potentially accelerate the discovery and establishment of an effective therapeutic treatment plan for COVID-19 patients.
PubMed: 33919660
DOI: 10.3390/pharmaceutics13040545 -
Cancer Research and Treatment Oct 2017Despite advancements in therapy for advanced gastric and gastroesophageal junction cancers, their prognosis remains dismal. Tumor angiogenesis plays a key role in cancer... (Review)
Review
Despite advancements in therapy for advanced gastric and gastroesophageal junction cancers, their prognosis remains dismal. Tumor angiogenesis plays a key role in cancer growth and metastasis, and recent studies indicate that pharmacologic blockade of angiogenesis is a promising approach to therapy. In this systematic review, we summarize current literature on the clinical benefit of anti-angiogenic agents in advanced gastric cancer. We conducted a systematic search of PubMed and conference proceedings including the American Society of Clinical Oncology, the European Society for Medical Oncology, and the European Cancer Congress. Included studies aimed to prospectively evaluate the efficacy and safety of anti-angiogenic agents in advanced gastric or gastroesophageal junction cancer. Each trial investigated at least one of the following endpoints: overall survival, progression-free survival/time to progression, and/or objective response rate. Our search yielded 139 publications. Forty-two met the predefined inclusion criteria. Included studies reported outcomes with apatinib, axitinib, bevacizumab, orantinib, pazopanib, ramucirumab, regorafenib, sorafenib, sunitinib, telatinib, and vandetanib. Second-line therapy with ramucirumab and third-line therapy with apatinib are the only anti-angiogenic agents so far shown to significantly improve survival of patients with advanced gastric cancer. Overall, agents that specifically target the vascular endothelial growth factor ligand or receptor have better safety profile compared to multi-target tyrosine kinase inhibitors.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Clinical Trials as Topic; Esophageal Neoplasms; Esophagogastric Junction; Humans; Molecular Targeted Therapy; Neoplasm Staging; Protein Kinase Inhibitors; Quality of Life; Receptor, ErbB-2; Stomach Neoplasms; Treatment Outcome; Vascular Endothelial Growth Factor A
PubMed: 28052652
DOI: 10.4143/crt.2016.176 -
Frontiers in Pharmacology 2023Papillary thyroid cancer (PTC) is the most common endocrine malignancy. However, different PTC variants reveal high heterogeneity at histological, cytological,...
Papillary thyroid cancer (PTC) is the most common endocrine malignancy. However, different PTC variants reveal high heterogeneity at histological, cytological, molecular and clinicopathological levels, which complicates the precise diagnosis and management of PTC. Alternative splicing (AS) has been reported to be potential cancer biomarkers and therapeutic targets. Here, we aim to find a more sophisticated molecular subclassification and characterization for PTC by integrating AS profiling. Based on six differentially expressed alternative splicing (DEAS) events, a new molecular subclassification was proposed to reclassify PTC into three new groups named as Cluster0, Cluster1 and Cluster2 respectively. An prediction was performed for accurate recognition of new groups with the average accuracy of 91.2%. Moreover, series of analyses were implemented to explore the differences of clinicopathology, molecular and immune characteristics across them. It suggests that there are remarkable differences among them, but Cluster2 was characterized by poor prognosis, higher immune heterogeneity and more sensitive to anti-PD1 therapy. The splicing correlation networks proved the complicated regulation relationships between AS events and splicing factors (SFs). An independent prognostic indicator for PTC overall survival (OS) was established. Finally, three compounds (orantinib, tyrphostin-AG-1295 and AG-370) were discovered to be the potential therapeutic agents. Overall, the six DEAS events are not only potential biomarkers for precise diagnosis of PTC, but also the probable prognostic predictors. This research would be expected to highlight the effect of AS events on PTC characterization and also provide new insights into refining precise subclassification and improving medical therapy for PTC patients.
PubMed: 36950012
DOI: 10.3389/fphar.2023.1119789 -
Frontiers in Oncology 2023Randomized controlled trials (RCTs) testing the combination therapy of transarterial chemoembolization (TACE) plus multikinase inhibitor (MKI) in patients with...
Transarterial chemoembolization with or without multikinase inhibitors for patients with unresectable hepatocellular carcinoma: a systematic review and meta-analysis of randomized controlled trials.
BACKGROUND
Randomized controlled trials (RCTs) testing the combination therapy of transarterial chemoembolization (TACE) plus multikinase inhibitor (MKI) in patients with unresectable hepatocellular carcinoma (HCC) have yielded inconsistent results.
METHODS
In this work, a systematic review and meta-analysis was performed to compare the TACE+MKI combination therapy versus TACE monotherapy in HCC patients with time to progression (TTP) adopted as primary outcome.
RESULTS
A total of 10 RCTs comprising 2837 patients receiving combination therapy (TACE plus sorafenib, brivanib, orantinib or apatinib) were included. TACE+MKI significantly prolonged TTP (hazard ratio [HR] 0.74, 95% CI 0.62-0.89, p=0.001) versus TACE monotherapy. Subgroup analysis suggested MKI administration before TACE might be preferable to post-TACE MKI for TTP. TACE+MKI also increased objective response rate (ORR) (risk ratio [RR] 1.17, 95% CI 1.03-1.32, p=0.01), but failed to improve overall survival (OS) (HR 0.98, 95% CI 0.86-1.13, p=0.82) and progression-free survival (PFS) (HR 0.75, 95% CI 0.50-1.12, p=0.16). The incidence of any adverse event (AE) did not significantly differ between TACE+MKI and TACE groups (RR 1.17, 95% CI 0.96-1.42, p=0.01), while serious AEs showed significant difference (RR 1.41, 95% CI 1.26-1.59, p<0.0001). Nevertheless, these AEs showing significant difference were mainly associated with MKI toxicities rather than TACE.
CONCLUSIONS
TACE+MKI combination therapy improved TTP and ORR but not OS and PFS in patients with unresectable HCC. Further high-quality trials are needed to verify these clinical benefits, and our findings could be very informative for future trial design.
PubMed: 37361570
DOI: 10.3389/fonc.2023.1139025 -
Oncology 2017The multikinase inhibitor sorafenib is the first oral molecular targeted agent with proven prognostic benefit in unresectable advanced hepatocellular carcinoma (HCC).... (Review)
Review
The multikinase inhibitor sorafenib is the first oral molecular targeted agent with proven prognostic benefit in unresectable advanced hepatocellular carcinoma (HCC). However, as with other drugs, sorafenib has its limitations, and various clinical trials have been conducted to develop novel molecular targeted agents for use alone or in combination with existing locoregional therapies. Despite this, clinical trials of molecular targeted agents combined with transarterial chemoembolization (TACE) have not reported major treatment outcomes to date. In this review, we describe previous clinical trials of combination therapy with TACE and a molecular targeted agent in patients with unresectable HCC.
Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Humans; Liver Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Sorafenib
PubMed: 29258086
DOI: 10.1159/000481243 -
International Journal of Oncology May 2017Prostate cancer is the second leading cause of cancer deaths among men in Western counties and has increased in incidence also in China in recent years. Although...
Prostate cancer is the second leading cause of cancer deaths among men in Western counties and has increased in incidence also in China in recent years. Although diagnosis modalities for primary prostate cancer have markedly improved, there are still no effective therapies for metastatic prostate cancer. SU6668 is an inhibitor of the tyrosine kinase activity of three angiogenic receptors VEGFR2, PDGFRβ and FGFR1. There is strong experimental evidence that SU6668 can induce growth inhibition of various primary tumors. However, the function and molecular mechanism of SU6668 in prostate cancer has not been fully elucidated. In the present study, we found that SU6668 inhibited the proliferation and invasion of prostate cancer cells. Functional studies also demonstrated that SU6668 inhibited epithelial-mesenchymal transition in DU145 and LNCap cells. After treatment with SU6668, MTDH protein, which has been reported to be significantly overexpressed in many human tumor tissues, was downregulated in DU145 and LNCap cells. siRNA-mediated silencing of MTDH in prostate cancer cells decreased their proliferation and invasive capabilities, suggesting that SU6668 may inhibit cell proliferation and invasion of prostate cancer cells partly through downstream targeting of MTDH. Mechanistic investigations showed that AKT signaling pathway was inhibited after SU6668 treatment in prostate cancer cells. Moreover, a combination of SU6668 and PI3K-AKT pathway inhibitor LY29004 resulted in increased inhibition of cell proliferation and invasion in DU145 cells. Taken together, our findings revealed that SU6668 suppressed prostate cancer progression by downregulating MTDH/AKT signaling pathway and identified a promising therapeutic strategy for prostate cancer.
Topics: Angiogenesis Inhibitors; Cell Adhesion Molecules; Cell Line, Tumor; Cell Proliferation; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Indoles; Male; Membrane Proteins; Neoplasm Invasiveness; Oxindoles; Propionates; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Pyrroles; RNA-Binding Proteins; Receptor, Fibroblast Growth Factor, Type 1; Receptor, Platelet-Derived Growth Factor beta; Signal Transduction; Vascular Endothelial Growth Factor Receptor-2
PubMed: 28339027
DOI: 10.3892/ijo.2017.3926 -
Cellular Physiology and Biochemistry :... 2017Recently, some small-molecule compounds that were designed for cancer therapy have acquired new roles in the treatment of pulmonary diseases. However, drug screening...
BACKGROUND/AIMS
Recently, some small-molecule compounds that were designed for cancer therapy have acquired new roles in the treatment of pulmonary diseases. However, drug screening aimed at abnormal muscle contraction is still limited. TSU-68 is a potent, orally administered, small-molecule agent that can reduce the vascular endothelial growth factor (VEGF)-induced Ca2+ increase in endothelial cells. We questioned whether TSU-68 could also affect calcium influx and relax airway smooth muscle (ASM) cells. The current study aimed to investigate these effects and to explore the underlying mechanisms.
METHODS
The effects of TSU-68 on ASM cells were studied in mice using a series of biophysiological techniques, including force measurement and patch-clamp experiments.
RESULTS
TSU-68 inhibited high K+ or acetylcholine chloride (ACh)-induced pre-contracted mouse tracheal rings in a concentration-dependent manner. Further research demonstrated that the TSU-68-induced ASM relaxation was mediated by calcium, which was decreased by blocking voltage-dependent Ca2+ channels (VDCCs) and non-selective cation channels (NSCCs).
CONCLUSION
Our data indicated that TSU-68 relaxes tense ASM by reducing the intracellular Ca2+ concentration through blocking VDCCs and NSCCs, which suggested that this small molecule might be useful in the treatment of abnormal smooth muscle.
Topics: Acetylcholine; Angiogenesis Inhibitors; Animals; Calcium; Calcium Channels; Cells, Cultured; Indoles; Male; Mice; Mice, Inbred BALB C; Muscle Contraction; Muscle Relaxation; Myocytes, Smooth Muscle; Oxindoles; Patch-Clamp Techniques; Potassium; Propionates; Pyrroles
PubMed: 28478457
DOI: 10.1159/000475653 -
Investigational New Drugs Oct 2014We aimed to investigate the recommended dose for the combination of TSU-68, a multiple-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor...
Phase I study on the safety, pharmacokinetic profile, and efficacy of the combination of TSU-68, an oral antiangiogenic agent, and S-1 in patients with advanced hepatocellular carcinoma.
PURPOSE
We aimed to investigate the recommended dose for the combination of TSU-68, a multiple-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2 and platelet-derived growth factor receptor-β, and S-1, an oral fluoropyrimidine, in patients with advanced hepatocellular carcinoma (HCC) based on its associated dose-limiting toxicity (DLT) frequency. We also determined the safety, tolerability, pharmacokinetics (PK), and efficacy of the combination treatment.
PATIENTS AND METHODS
Patients without any prior systemic therapy received 400 mg/day TSU-68 orally and 80 mg/day (level 1) or 100 mg/day (level 2) S-1 for 4 or 2 weeks followed by a 2- or 1-week rest period (groups A and B, respectively). According to the treatment, patients progressed from level 1B to level 2A, then level 2B. Safety and response rates were assessed.
RESULTS
Eighteen patients were enrolled. Two patients at levels 1B and 2A but none at level 2B showed DLTs. The common adverse drug reactions were a decrease in hemoglobin levels, hypoalbuminemia, and anorexia, which were mild in severity (grades 1-2). PK data from levels 1B and 2A indicated that the area under the curve for TSU-68 and 5-fluorouracil was unlikely to be affected by the combination treatment. Response rate, disease control rate, median time to progression, and median overall survival were 27.8 %, 61.1 %, 5.3 months, and 12.8 months, respectively.
CONCLUSION
The recommended dose for advanced HCC should be 400 mg/day TSU-68 and 100 mg/day S-1 for 4 weeks followed by 2-week rest.
Topics: Administration, Oral; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Drug Combinations; Female; Humans; Indoles; Liver Neoplasms; Male; Middle Aged; Oxindoles; Oxonic Acid; Propionates; Pyrroles; Tegafur; Treatment Outcome
PubMed: 24829073
DOI: 10.1007/s10637-014-0109-2 -
Cancer Research and Treatment Apr 2016This study analyzed the role of plasma biomarkers for TSU-68 in a previous phase II trial comparing TSU-68 plus docetaxel and docetaxel alone in patients with metastatic...
PURPOSE
This study analyzed the role of plasma biomarkers for TSU-68 in a previous phase II trial comparing TSU-68 plus docetaxel and docetaxel alone in patients with metastatic breast cancer.
MATERIALS AND METHODS
A total of 77 patients were eligible for this study (38 in the TSU-68 plus docetaxel arm and 39 in the docetaxel alone arm). Blood samples were collected prior to the start of each cycle, and vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF)-AA, -AB, -BB, fibroblast growth factor, M30, C-reactive protein (CRP), and interleukin 6 (IL-6) levels were measured using enzyme linked immunosorbent assay. The primary endpoint was progression-free survival (PFS).
RESULTS
In patients with baseline PDGF-AA ≥ median, median PFS was significantly worse in the TSU-68 plus docetaxel group than in the docetaxel alone group (5.4 months vs. 13.7 months, p=0.049), while a trend toward a PFS benefit was observed in those with baseline PDGF-AA < median (9.7 months vs. 4.0 months, p=0.18; p for interaction=0.03). In the TSU-68 plus docetaxel group, PFS showed significant association with fold changes in CRP (p=0.001), IL-6 (p < .001), PDGF-BB (p=0.02), and VEGF (p=0.047) following the first treatment cycle.
CONCLUSION
Baseline PDGF-AA levels and dynamics of VEGF, PDGF-BB, CRP, and IL-6 levels were predictive for the efficacy of TSU-68.
Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; C-Reactive Protein; Docetaxel; Enzyme-Linked Immunosorbent Assay; Female; Fibroblast Growth Factors; Humans; Indoles; Interleukin-6; Middle Aged; Neoplasm Metastasis; Oxindoles; Propionates; Pyrroles; Taxoids; Vascular Endothelial Growth Factor A
PubMed: 26194374
DOI: 10.4143/crt.2015.089