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Introduction: The incidence of mesothelioma is rising. First-line cisplatin and pemetrexed confers a survival benefit, with a median progression-free survival (PFS) of 5.7 months. Sorafenib inhibits tyrosine kinases, including rec...
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Introduction: The incidence of mesothelioma is rising. First-line cisplatin and pemetrexed confers a survival benefit, with a median progression-free survival (PFS) of 5.7 months. Sorafenib inhibits tyrosine kinases, including receptors for vascular endothelial growth factor, which are implicated in mesothelioma pathogenesis by preclinical and clinical data. Methods: Sorafenib, at 400 mg twice daily, was assessed in a single- arm multicenter phase 2 study, using Simon's two-stage design. Eligible patients had received platinum combination chemotherapy earlier. The primary endpoint was PFS at 6 months, with secondary endpoints, including response rate and metabolic response, assessed using fluorodeoxyglucose positron emission tomography. Published reference values for PFS in mesothelioma provide a benchmark for the null hypothesis of 28% progression-free at 6 months, and for moderate or significant clinical activity of 35% or 43% progressionfree at 6 months, respectively. Results: Fifty-three patients (72%) were treated. Most had epithelioid histology. Ninety-three percent of patients had a performance status 0 or 1. Treatment was well tolerated with few grade 3 or 4 toxicities. Median PFS was 5.1 months, with 36% of patients being progression-free at 6 months. Nine percent of patients remained on study beyond 1 year. Changes in fluorodeoxyglucose positron emission tomography parameters did not predict clinical outcome. Conclusions: Sorafenib is well tolerated in patients with mesothelioma after completion of platinum-containing chemotherapy. PFS of sorafenib compares favorably with that reported for other targeted agents, and suggests moderate activity in this disease.
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Background: MOST (My Own Specific Therapy) is a prospective, randomized, open-label, adaptive phase II trial conducted in patients (pts) with progressive solid tumors (any subtype) after at least one prior therapy in advanced sett...
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Background: MOST (My Own Specific Therapy) is a prospective, randomized, open-label, adaptive phase II trial conducted in patients (pts) with progressive solid tumors (any subtype) after at least one prior therapy in advanced setting. This trial aims to evaluate the clinical benefit of therapies targeting molecular alterations identified in the patient’s tumor. NovellusDx’ technology measures the functional impact of alterations including Variants of Uncertain Significance (VUS), and TA efficacy based on NGS findings. Methods: Pts were treated with sorafenib 400 mg BID based on KRAS/KDR, HRAS and BRAF (non-V600) oncogenic mutations/amplification. After 12 weeks of treatment (induction period), pts with stable disease were randomly assigned to continuation or interruption of sorafenib. NGS data from the treated pts were blindly analyzed by the functional assay: synthesized mutated genes and florescent reporter genes were transfected into live cells and scanned in a microscopy system. The specific pathways activation was evaluated by quantifying the subcellular localization of the reporter proteins. Sorafenib response prediction based on the assay was compared with the best change tumor size assessed in the MOST trial, and the maintenance treatment duration. Results: 17 patients treated for at least 12 weeks with sorafenib were analyzed. Tumor genomic alterations that indicated the sorafenib treatment consisted in KRAS mutations (n ? 9), KRAS amplifications (n ? 3), HRAS mutation (n ? 3), KDR amplification/mutation (n ? 2). However, NGS data showed additional molecular aberrations. Of which, the functional impact and response to TA of 18 unique variants in 10 different genes was measured. The correlation between the assay-based response prediction and the variation in the tumor volume of the patients will be presented. Conclusions: Multidisciplinary molecular tumor board recommends TA based on single actionable oncogenic mutations. Taking into account significant other genomic variants is crucial to accurately predict targeted agent efficacy.
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Background: A recent Phase I study of metronomic oral vinorelbine (60mg, 90mg and 120mg) per week and 200mg BID sorafenib in Asian NSCLC patients performed by our group showed that the combination of 60mg/week vinorelbine and 200m...
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Background: A recent Phase I study of metronomic oral vinorelbine (60mg, 90mg and 120mg) per week and 200mg BID sorafenib in Asian NSCLC patients performed by our group showed that the combination of 60mg/week vinorelbine and 200mg BID sorafenib correlated with better survival and response. We herein report the pharmacokinetics (PK) profile of metronomic vinorelbine at these three doses in combination with 200mg BID sorafenib in Asian NSCLC patients to better understand the pharmacology of this low dose combination treatment.
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The tyrosine kinase inhibitor drug sorafenib is used in the treatment of liver and renal cancers but adverse effects may necessitate dose interruption and under-dosage may lead to therapeutic failure. Sorafenib also undergoes cyto...
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The tyrosine kinase inhibitor drug sorafenib is used in the treatment of liver and renal cancers but adverse effects may necessitate dose interruption and under-dosage may lead to therapeutic failure. Sorafenib also undergoes cytochrome P450 (CYP)-dependent biotransformation to the N-oxide and other metabolites. However, although CYPs are major determinants of efficacy and toxicity the roles of these enzymes in the formation of multiple sorafenib metabolites are unclear. In the present study CYP-mediated pathways of sorafenib oxidation in human liver were evaluated. cDNA-expressed CYP3A4 was the major catalyst in the formation of the principal N-oxide and N-hydroxymethyl metabolites of sorafenib, as well as the minor N-desmethyl metabolite. In contrast, CYP3A5 exhibited only ～5% of the activity of CYP3A4 and eleven other CYPs and three flavin-containing monooxygenases were inactive. In human hepatic microsomes metabolite formation was correlated with CYP3A4-mediated midazolam 1′-hydroxylation, but not with other CYP-specific substrate oxidations. In accord with these findings the CYP3A4 inhibitor ketoconazole selectively inhibited microsomal sorafenib oxidation pathways. From computational modeling studies atoms in the structure of sorafenib that undergo biotransformation were within ～5.4 of the CYP3A4 heme. Important hydrogen bonding interactions between sorafenib and amino acids Ser-119 and Glu-374 in the active center of CYP3A4 were identified. These findings indicate that sorafenib is oxidized selectively by human CYP3A4. This information could be adapted in individualized approaches to optimize sorafenib safety and efficacy in cancer patients.
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Abstract Background and Aim The Albumin‐Bilirubin (ALBI) grade is a new index to assess objectively liver function and prognosis in patients with hepatocellular carcinoma (HCC). This study aimed to elucidate the application of AL...
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Abstract Background and Aim The Albumin‐Bilirubin (ALBI) grade is a new index to assess objectively liver function and prognosis in patients with hepatocellular carcinoma (HCC). This study aimed to elucidate the application of ALBI grade in baseline and sorafenib‐end in advanced HCC patients who received sorafenib. Methods A total of 415 consecutive advanced HCC patients in Child–Pugh A received sorafenib in our hospital. Sorafenib was terminated when radiologic tumor progression or clinical liver function deterioration (LD) occurred in the reassessment bimonthly. Patients who failed with sorafenib monotherapy were retrospectively analyzed. Results A total of 260 (62.6%) patients were enrolled, including 98 (37.7%) ALBI grade I and 162 (62.3%) grade II in baseline. More patients in ALBI grade II stopped sorafenib because of LD than in grade I (33.3% vs 14.3%, P ?<?0.001). Those who in baseline ALBI grade I had a superior overall survival than in grade II (8.5?months vs 4.4?months, P ?=?0.003). Cox regression analysis confirmed that baseline ALBI grade II ( P ?<?0.001) and ALBI grade increase during treatment ( P ?<?0.001) strongly contributed to the mortality of HCC patients who received sorafenib. After sorafenib failure, those with post‐sorafenib treatment had a better post‐sorafenib survival than those without (9.3 vs 1.6?months, P ?<?0.001). Logistic regression analysis indicated that sorafenib‐end ALBI grade and LD occurrence were the only two predictors of post‐sorafenib treatment after sorafenib failure. Conclusions In clinical practice, we firstly demonstrated that not only ALBI grade in baseline but also ALBI grade change during treatment could predict the prognosis of advanced HCC patients who received sorafenib.
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Background: The purpose of this study was to clarify the molecular regulatory mechanism of c-Met up-regulated expression and elucidate the molecular mechanisms by which c-Met overexpression and activation drive progression and sor...
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Background: The purpose of this study was to clarify the molecular regulatory mechanism of c-Met up-regulated expression and elucidate the molecular mechanisms by which c-Met overexpression and activation drive progression and sorafenib resistance in hepatocellular carcinoma (HCC). Methods: The resistance index was calculated. Bioinformatic techniques were applied to predict the transcription factors that bind and their binding sites on the c-Met promoter. Chromatin immunoprecipitation assays were implemented to verify the prediction results. To determine the regulatory mechanisms and effects of c-Met on sorafenib resistance in HCC, c-Met expression and activation were down-regulated by siRNA and inhibitor in in vivo and vitro experiments, while a parental cell line (Huh-7) was transfected with the adenovirus that upregulated c-Met expression. Results: c-Met expression was increased in HCC sorafenib-resistant cells. Functional findings suggested that c-Met overexpression and activation drive HCC tumor progression and sorafenib resistance by promoting cell proliferation, migration, and stopping apoptosis. Molecular mechanism findings demonstrated that the MEK/ERK signaling pathway activated the expression and activity of ETS-1 mediated by p-ERK, which led to its binding to the c-Met gene promoter and upregulation of c-Met transcriptional expression. The activation of the HGF/c-Met pathway drives sorafenib resistance in HCC cells by activating the Ras/Raf/ERK and PI3K/Akt signaling pathways, which regulate biologic processes, including cell proliferation, migration and anti-apoptosis. Conclusion: c-Met overexpression and activation is an essential mechanism of sorafenib resistance in HCC. Combination therapy of sorafenib plus c-Met inhibitor overcame the resistance of sorafenib-targeted therapy for HCC.
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Die Hemmung des Gefäßwachstums (Angiogenese) stellt eine neue Therapieoption in der modernen Onkologie dar. Zum ersten Mal überhaupt zielt eine therapeutische Substanz auf die Tumorumgebung und nicht auf die Tumorzellen selbst ...
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Die Hemmung des Gefäßwachstums (Angiogenese) stellt eine neue Therapieoption in der modernen Onkologie dar. Zum ersten Mal überhaupt zielt eine therapeutische Substanz auf die Tumorumgebung und nicht auf die Tumorzellen selbst ab. Im Fokus liegt das Schlüsselmolekül der Gefäßneubildung VEGF („vascular endothelial growth factor“). VEGF- und VEGF-Rezeptor-inhibierende Medikamente haben in Kombination mit Chemotherapie und als Monotherapie Eingang in die klinische Praxis gefunden und in den letzten Jahren das Feld der systemischen Krebstherapie maßgeblich beeinflusst. Dennoch sind viele grundlagenwissenschaftliche und klinische Fragen nach wie vor ungeklärt. Auch sind der Wirkmechanismus der zugelassenen Medikamente sowie insbesondere die Limitationen beim Einsatz von antiangiogenen Substanzen bislang noch nicht hinreichend erforscht. Dieser Artikel gibt einen Überblick über die wichtigsten angiogenetischen Mechanismen und Signalkaskaden, die derzeit in der Klinik eingesetzten antiangiogenen Medikamente und den aktuellen Stand der präklinischen Forschung auf dem Weg in die klinische Anwendung.
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Background: Acquired resistance to sorafenib in hepatocellular carcinoma (HCC) patients results in poor prognosis. Epithelial-to-mesenchymal transition (EMT) is the major mechanism implicated in the resistance to sorafenib. We hav...
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Background: Acquired resistance to sorafenib in hepatocellular carcinoma (HCC) patients results in poor prognosis. Epithelial-to-mesenchymal transition (EMT) is the major mechanism implicated in the resistance to sorafenib. We have reported the tumor suppressor role of SLAMF3 (signaling lymphocytic activation molecules family 3) in HCC progression and highlighted its implication in controlling the MRP-1 transporter activity. These data suggest the implication of SLAMF3 in sorafenib resistance mechanisms. Methods: We evaluated the resistance to sorafenib in Huh-7 cells treated with progressive doses (Res cells). We investigated the link between acquired resistance to sorafenib and SLAMF3 expression by flow cytometry and Western blot methods. Furthermore, we analyzed the EMT and the stem cell potential of cells resistant to sorafenib. Results: Sorafenib resistance was confirmed in Res cells by analyzing the cell viability in the presence of sorafenib. The mesenchymal transition, in Res cells, was confirmed by high migratory index and the expression of EMT antigens. Interestingly, we found that loss of SLAMF3 expression corresponded to sorafenib-resistant phenotypes. The overexpression of SLAMF3 reversed EMT, decreased metastatic potential and inhibited mTOR/ERK1/2 in Res cells. Conclusions: We propose that rescuing SLAMF3 expression in resistant cells could represent a potential therapeutic strategy to enhance sorafenib efficacy in HCC patients.
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Sorafenib is a multikinase inhibitor widely used in cancer therapy with an antitumour effect related to biological processes as proliferation, migration or invasion, among others. Initially designed as a Raf inhibitor, Sorafenib w...
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Sorafenib is a multikinase inhibitor widely used in cancer therapy with an antitumour effect related to biological processes as proliferation, migration or invasion, among others. Initially designed as a Raf inhibitor, Sorafenib was later shown to also block key molecules in tumour progression such as VEGFR and PDGFR. In addition, sorafenib has been connected with key signalling pathways in cancer such as EGFR/EGF. However, no definitive clue about the molecular mechanism linking sorafenib and EGF signalling pathway has been established so far. Our data in HeLa, U2OS, A549 and HEK293T cells, based on in silico, chemical and genetic approaches demonstrate that the MEK5/ERK5?signalling pathway is a novel target of sorafenib. In addition, our data show how sorafenib is able to block MEK5-dependent phosphorylation of ERK5 in the Ser218/Tyr220, affecting the transcriptional activation associated with ERK5. Moreover, we demonstrate that some of the effects of this kinase inhibitor onto EGF biological responses, such as progression through cell cycle or migration, are mediated through the effect exerted onto ERK5?signalling pathway. Therefore, our observations describe a novel target of sorafenib, the ERK5?signalling pathway, and establish new mechanistic insights for the antitumour effect of this multikinase inhibitor.
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