Combination Foretinib and Anti-PD-1 Antibody Immunotherapy for Colorectal Carcinoma
Immune checkpoint inhibitors have achieved unprecedented success in cancer immunotherapy. However, the overall response rate to immune checkpoint inhibitor therapy for many cancers is only between 20 and 40%, and even less for colorectal cancer (CRC) patients. Thus, there is an urgent need to develop an efficient immunotherapeutic strategy for CRC. Here, we developed a novel CRC combination therapy consisting of a multiple receptor tyrosine kinase inhibitor (Foretinib) and anti-PD-1 antibody.
The combination therapy significantly inhibited tumor growth in mice, led to improved tumor regression without relapse (83% for CT26 tumors and 50% for MC38 tumors) and prolonged overall survival. Mechanistically, Foretinib caused increased levels of PD-L1 via activating the JAK2-STAT1 pathway, which could improve the effectiveness of the immune checkpoint inhibitor.
Moreover, the combination therapy remodeled the tumor microenvironment and enhanced anti-tumor immunity by further increasing the infiltration and improving the function of T cells, decreasing the percentage of tumor-associated macrophages (TAMs) and inhibiting their polarization toward the M2 phenotype. Furthermore, the combination therapy inhibited the metastasis of CT26-Luc tumors to the lung in BALB/c mouse by reducing proportions of regulatory T-cells, TAMs and M2 phenotype TAMs in their lungs. This study suggests that a novel combination therapy utilizing both Foretinib and anti-PD-1 antibody could be an effective combination strategy for CRC immunotherapy.
Targeted dual inhibition of c-Met/VEGFR2 signalling by foretinib improves antitumour effects of nanoparticle paclitaxel in gastric cancer models
- Elevated expression of multiple growth factors and receptors including c-Met and VEGFR has been reported in gastric adenocarcinoma (GAC) and thus provides a potentially useful therapeutic target. The therapeutic efficacy of foretinib, a c-Met/VEGFR2 inhibitor, was determined in combination with nanoparticle paclitaxel (NPT) in GAC. Animal studies were conducted in NOD/SCID mice in subcutaneous and peritoneal dissemination xenografts. The mechanism of action was assessed by Immunohistochemical and Immunoblot analyses.
- In c-Met overexpressing MKN-45 cell-derived xenografts, NPT and foretinib demonstrated inhibition in tumour growth, while NPT plus foretinib showed additive effects. In c-Met low-expressing SNU-1 or patient-derived xenografts, the foretinib effect was smaller, while NPT had a similar effect compared with MKN-45, as NPT plus foretinib still exhibited an additive response. Median mice survival was markedly improved by NPT (83%), foretinib (100%) and NPT plus foretinib (230%) in peritoneal dissemination xenografts. Subcutaneous tumour analyses exhibited that foretinib increased cancer cell death and decreased cancer cell proliferation and tumour vasculature. NPT and foretinib suppressed the proliferation of GAC cells in vitro and had additive effects in combination. Further, foretinib caused a dramatic decrease in phosphorylated forms of c-Met, ERK, AKT and p38.
- Foretinib led to a decrease in Bcl-2, and an increase in p27, Bax, Bim, cleaved PARP-1 and cleaved caspase-3. Thus, these findings highlight the antitumour impact of simultaneous suppression of c-Met and VEGFR2 signalling in GAC and its potential to enhance nanoparticle paclitaxel response. This therapeutic approach might lead to a clinically beneficial combination to increase GAC patients’ survival.
Response surface methodology for optimization of micellar-enhanced spectrofluorimetric method for assay of foretinib in bulk powder and human urine
This work investigates a sensitive and precise enhanced spectrofluorimetric assay for assay of foretinib (FTB); a tyrosine kinase inhibitor drug used for treatment of breast cancer, in tablets and urine through response surface optimization by micelle mediated protocol. The basis of the described method is the enhancement of the fluorescence behavior of FTB in Cremophor RH 40 (Cr RH 40) micellar medium and measuring the fluorescence of FTB at 344 nm after excitation at 245 nm. Optimization was performed through evaluation of diluting solvent, types of organized media, buffer type and its relevant pH.
Response surface methodology was applied to obtain the optimized values of variables that mostly affect interaction of Cr RH 40 with FTB using Box-Behnken design. ICH guidelines were adhered for the validation of merit figures. Acceptable linear relationship was obtained between relative fluorescence intensity (RFI) and FTB concentrations in the range of 50 – 1000 µg L-1, with correlation coefficient of 0.998. Accuracy was ≥ 99.82% and calculated limit of detection (LOD) was 10.60 µg L-1. Method applications included FTB assaying in pure bulk powder. Furthermore, applications on urine samples were performed with accuracy of 100.59 ± 3.40%. The method represents echo-friendly approach and effective alternating methodology to the relevant analytical ones for FTB assaying.
Foretinib induces G2/M cell cycle arrest, apoptosis, and invasion in human glioblastoma cells through c-MET inhibition
Purpose: Glioblastoma multiforme (GBM) is one of the most aggressive human cancers. The c-MET receptor tyrosine kinase (RTK) which is frequently deregulated in GBM is considered as a promising target for GBM treatment. The c-MET plays a key role in cell proliferation, cell cycle progression, invasion, angiogenesis, and metastasis. Here, we investigated the anti-tumour activity of foretinib, a c-MET inhibitor, on three human GBM cells (T98G, U87MG and U251).
Methods: Anti-proliferative effect of foretinib was determined using MTT, crystal violet staining, and clonogenic assays. PI and Annexin V/PI staining flow cytometry were used to evaluate the effects of foretinib on cell cycle and apoptosis, respectively. Scratch assay, qRT-PCR, western blot, and zymography analyses were applied to elucidate the molecular mechanisms underlying the anti-tumour activity of foretinib.
Results: Foretinib treatment reduced phosphorylation of c-MET on T98G and U251 cells, but not in U87MG cells. The highest inhibitory effect was observed in T98G cells (IC50 = 4.66 ± 0.29 µM) and the lowest one in U87MG cells (IC50 = 29.99 ± 1.31 µM). The results showed that foretinib inhibited the proliferation of GBM cells through a G2/M cell cycle arrest and mitochondrial-mediated apoptosis in association with alternation in expression of the related genes and protein-regulated G2/M phase and apoptosis. Foretinib diminished GBM cell invasion through downregulation of the proteolytic cascade of MMP2, uPA and uPAR and epithelial-mesenchymal transition (EMT)-related genes. A different GBM cell sensitivity pattern was noticeable in all experiments which demonstrated T98G as a sensitive and U87MG as a resistant phenotype to foretinib treatment.
Conclusion: The results indicated that foretinib might have the therapeutic potential against human GBM which deserve further investigation.
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| 9476-25 | Biovision | each | 548.4 EUR |
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| 9476-5 | Biovision | each | 183.6 EUR |
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| 201372 | MedKoo Biosciences | 50.0mg | 120 EUR |
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| GP7709 | Glentham Life Sciences | 1mg | 563.66 EUR |
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| F691200 | Toronto Research Chemicals | 100mg | 164 EUR |
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| MBS132214-100mg | MyBiosource | 100mg | 1065 EUR |
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| MBS132214-500mg | MyBiosource | 500mg | 2775 EUR |
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| HY-10338 | MedChemExpress | 10mM/1mL | 176.4 EUR |
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| GP7709-1 | Glentham Life Sciences | 1 | 212.7 EUR |
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| GP7709-10 | Glentham Life Sciences | 10 | 516.9 EUR |
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| GP7709-5 | Glentham Life Sciences | 5 | 303.5 EUR |
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| T3113-10mg | TargetMol Chemicals | 10mg | Ask for price |
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| T3113-1g | TargetMol Chemicals | 1g | Ask for price |
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| T3113-1mg | TargetMol Chemicals | 1mg | Ask for price |
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| T3113-50mg | TargetMol Chemicals | 50mg | Ask for price |
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| T3113-5mg | TargetMol Chemicals | 5mg | Ask for price |
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| MBS578171-100mg | MyBiosource | 100mg | 395 EUR |
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| MBS578171-10mg | MyBiosource | 10mg | 160 EUR |
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| MBS578171-25mg | MyBiosource | 25mg | 210 EUR |
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| MBS578171-50mg | MyBiosource | 50mg | 270 EUR |
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| MBS578171-5mg | MyBiosource | 5mg | 145 EUR |
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| MBS3606162-100mg | MyBiosource | 100mg | 415 EUR |
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| MBS3606162-10mg | MyBiosource | 10mg | 210 EUR |
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| MBS3606162-25mg | MyBiosource | 25mg | 245 EUR |
Development of innovative artificial neural networks for simultaneous determination of lapatinib and foretinib in human urine by micellar enhanced synchronous spectrofluorimetry
A highly selective and simple micellar synchronous spectrofluorimetric method was described for simultaneous analysis of two tyrosine kinase inhibitors (TKIs); namely lapatinib (LPB) and foretinib (FTB) in human urine. The method depended on measuring synchronous fluorescence of the two drugs in micellar media composed of cremophor RH 40 (Cr RH 40) surfactant using feed-forward and cascade-forward neural networks preceded by genetic algorithm for data manipulation. Different experimental conditions that affect fluorescence of the cited drugs are optimized including pH, diluting solvent, surfactant’s type and concentration.
A training set of nine mixtures containing different concentrations of both drugs was prepared for models’ construction. Extra validation set composed of other nine mixtures was prepared to validate prediction performance for the constructed models. Root mean square error of prediction (RMSEP) was used as a tool to compare prediction power of each model. The method was extended for quantification of LPB and FTB in spiked human urine.