-
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 -
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 -
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 -
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 -
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 -
Chinese Clinical Oncology Dec 2013Approximately 32,000 patients die of primary liver cancer each year in Japan. The annual number of deaths from primary liver cancer in Japan ranks second only to that in...
Approximately 32,000 patients die of primary liver cancer each year in Japan. The annual number of deaths from primary liver cancer in Japan ranks second only to that in China in the world. In recent years, there has been a gradual trend towards decrease in the number of liver cancer patients from its peak in Japan, and this trend is expected to also continue in the future. The main reason for this decreasing trend was the establishment of screening of transfusion products for hepatitis B and hepatitis C viruses, which prevents transfusion-related transmission of the viral infection. Most patients with hepatocellular carcinoma (HCC) in Japan have underlying viral hepatitis, with hepatitis C accounting for about two-third of all the patients and hepatitis B accounting for about 15%. Regular screening of patients with viral hepatitis infection makes it possible to diagnose HCC early, and also enables effective loco-regional treatment, such as surgical resection, local ablative therapy and transcatheter arterial chemoembolization (TACE). However, HCC recurrence is encountered frequently even after these potentially effective treatments. After numerous loco-regional treatments for recurrent HCC, chemotherapy is administered for patients with highly advanced HCC. Among the modalities of chemotherapy, hepatic arterial infusion chemotherapy (HAIC) is employed more commonly than systemic chemotherapy, although no survival advantage has ever been demonstrated. Randomized controlled studies are currently under way to clarify the survival benefit of HAIC. Also, various novel systemic chemotherapeutic agents are currently under development in Japan, and further improvements in the treatment outcomes are expected.
PubMed: 25841919
DOI: 10.3978/j.issn.2304-3865.2013.09.01 -
Molecular & Cellular Proteomics : MCP Sep 2012The most common mutation in cystic fibrosis (CF) is a deletion of Phe at position 508 (ΔF508-CFTR). ΔF508-CFTR is a trafficking mutant that is retained in the ER,...
The most common mutation in cystic fibrosis (CF) is a deletion of Phe at position 508 (ΔF508-CFTR). ΔF508-CFTR is a trafficking mutant that is retained in the ER, unable to reach the plasma membrane. To identify compounds and drugs that rescue this trafficking defect, we screened a kinase inhibitor library enriched for small molecules already in the clinic or in clinical trials for the treatment of cancer and inflammation, using our recently developed high-content screen technology (Trzcinska-Daneluti et al. Mol. Cell. Proteomics 8:780, 2009). The top hits of the screen were further validated by (1) biochemical analysis to demonstrate the presence of mature (Band C) ΔF508-CFTR, (2) flow cytometry to reveal the presence of ΔF508-CFTR at the cell surface, (3) short-circuit current (Isc) analysis in Ussing chambers to show restoration of function of the rescued ΔF508-CFTR in epithelial MDCK cells stably expressing this mutant (including EC(50) determinations), and importantly (4) Isc analysis of Human Bronchial Epithelial (HBE) cells harvested from homozygote ΔF508-CFTR transplant patients. Interestingly, several inhibitors of receptor Tyr kinases (RTKs), such as SU5402 and SU6668 (which target FGFRs, VEGFR, and PDGFR) exhibited strong rescue of ΔF508-CFTR, as did several inhibitors of the Ras/Raf/MEK/ERK or p38 pathways (e.g. (5Z)-7-oxozeaenol). Prominent rescue was also observed by inhibitors of GSK-3β (e.g. GSK-3β Inhibitor II and Kenpaullone). These results identify several kinase inhibitors that can rescue ΔF508-CFTR to various degrees, and suggest that use of compounds or drugs already in the clinic or in clinical trials for other diseases can expedite delivery of treatment for CF patients.
Topics: Animals; Benzazepines; Cell Line; Cricetinae; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dogs; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; HEK293 Cells; Humans; Indoles; Ion Transport; Membrane Proteins; Oxindoles; Propionates; Protein Kinase Inhibitors; Protein Transport; Protein-Tyrosine Kinases; Pyrroles; RNA Interference; RNA, Small Interfering; Receptor, Fibroblast Growth Factor, Type 1; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Sequence Deletion; Signal Transduction; Zearalenone
PubMed: 22700489
DOI: 10.1074/mcp.M111.016626 -
British Journal of Cancer Oct 2013This study aimed to determine whether combination S-1 plus cisplatin (CDDP) therapy, the most widely used therapy for Japanese patients with advanced gastric cancer, and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
This study aimed to determine whether combination S-1 plus cisplatin (CDDP) therapy, the most widely used therapy for Japanese patients with advanced gastric cancer, and the novel oral antiangiogenic agent TSU-68 could contribute to gastric cancer treatment.
METHODS
Ninety-three patients with chemotherapy-naïve unresectable or recurrent advanced gastric cancers were randomised into two groups: TSU-68 plus S-1/CDDP (group A) and S-1/CDDP (group B) groups. Both patient groups received identical S-1 and CDDP dosages. TSU-68 was orally administered for 35 consecutive days. Group B patients received S-1 orally twice daily for three consecutive weeks, followed by intravenous CDDP on day 8. The primary endpoint was progression-free survival (PFS).
RESULTS
Median PFS periods were 208 and 213 days in groups A and B, respectively (P=0.427). Median survival periods for groups A and B were 497.0 and 463.5 days, respectively (P=0.219). No statistically significant differences were noted for PFS, survival or the adverse event (AE) incidence rate. All AEs were expected according to previous reports for TSU-68, TS-1, and CDDP.
CONCLUSION
Combination therapy involving TSU-68, S-1, and CDDP was safe and well tolerated in patients with chemotherapy-naïve unresectable or recurrent advanced gastric cancers. However, factors related to therapeutic efficacy should be investigated further.
Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Disease-Free Survival; Drug Combinations; Female; Humans; Indoles; Male; Middle Aged; Oxindoles; Oxonic Acid; Propionates; Pyrroles; Stomach Neoplasms; Survival Rate; Tegafur
PubMed: 24045669
DOI: 10.1038/bjc.2013.555 -
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