Administration Of Sorafenib Research Articles

Pharmacogenomics of Sorafenib in Liver Cancer

Liver cancer is one of the most challenging cancers to diagnose and treat. Sorafenib is a tyrosine kinase inhibitor (TKI) which is prescribed in advanced or unresctable liver cancer. While this drug is one of the already-limited choices for liver cancer treatment, sorafenib-resistance and variation in therapeutic response adds more to the treatment difficulties. There are various ways in which cancer cells are able to out-smart these drugs; genetic polymorphism is one of the ways through which the mechanisms of varied response to sorafenib can be comprehended. Notably, studies including genes involved in pharmacokinetics of sorafenib like ATP binding cassette subfamily B member 1 (ABCB1 rs2032582, rs1045642), ATP binding cassette subfamily G member 2 (ABCG2 rs2231137, rs2231142, rs2622604), ATP binding cassette subfamily C member 2 (ABCC2/ MRP2 rs3740066), UDP glucuronosyltransferase family 1 member A1 (UGT1A1 rs8175347), UDP glucuronosyltransferase family 1 member A9 (UGT1A9 rs17868320, rs72551330, rs6714486), Cytochrome p450 system ( CYP3A5*3 rs776746), (CYP3A4 rs2740574), (CYP26A1 rs7905939), Solute carrier organic anion transporter family member 1 B1 (SLCO1B1 rs2306283, rs4149056), Solute carrier family 22 member 14 (SLC22A14 rs149738, rs171248, rs183574), Solute carrier family 15 member 2 (SLC15A2 rs2257212) in addition to genes involved in agiogenesis, like Nitric oxide synthase 3 /Endothelial NOS (NOS3/eNOS rs2070744, rs2070744, rs2070744, rs61722009, rs1799983), Vascular endothelial growth factor A (VEGF-A rs25648, rs833061, rs699947, rs2010963), Vascular endothelial growth factor C (VEGF-C rs4604006, rs664393), kinase insert domain receptor (KDR/VEGFR-2 rs2071559, rs2305948, rs1870377, rs4864950), Hypoxia inducible factor 1 subunit alpha (HIF-1A rs1951795, rs10873142, rs12434438, rs12434438), Fibroblast growth factor 2 (FGF2 rs308379, rs308447) were analyzed in this article. Some of these SNPs were associated with favorable therapeutic outcomes, while others correlated with resistance or adverse events (AEs) due to sorafenib administration. Some AEs showed counter-intuitive results i.e. association with improved overall survival (OS) and progression-free survival (PFS) This review article aims to exhaustively study and analyze the mechanisms involved in variation of sorafenib therapeutic response.

Outcomes of Children and Adolescents with Acute Myeloid Leukemia and FLT3-ITD Treated with Low- or Standard-Dose Chemotherapy Plus Sorafenib on the Cals III-AML18 Trial (ChiCTR1800015883)

Background: FLT3 -ITD mutations are linked to a poor prognosis in pediatric acute myeloid leukemia (AML). Combining targeted therapies, such as sorafenib, with chemotherapy may enhance outcomes for these patients. Low-dose chemotherapy (LDC) has demonstrated safety and effectiveness in some cases. We aimed to investigate whether combining LDC or standard-dose chemotherapy (SDC) with sorafenib can improve the prognosis of patients with FLT3-ITD-positive AML. Methods: From June 2018 to June 2022, this multicenter clinical trial enrolled 497 children with newly diagnosed acute myeloid leukemia (AML), who were randomly assigned to receive either low-dose chemotherapy (LDC) or standard-dose chemotherapy (SDC). Among these, 60 patients were positive for FLT3-ITD mutations. Sorafenib was administered based on recommendations of physicians at a dosage of 200 mg/m²/day. We compared clinical characteristics and outcomes between patients receiving sorafenib (n=40) and those not receiving sorafenib (n=20), focusing on rates of complete morphologic remission with or without platelet recovery (CR/CRi), overall survival (OS), and event-free survival (EFS). Results: There were no significant differences in clinical and biological characteristics between the sorafenib and non-sorafenib groups. Of the 60 patients with AML harboring FLT3-ITD mutations, 33 received sorafenib starting from Induction I. After Induction I, complete morphologic remission with or without platelet recovery (CR/CRi) was achieved in 48.5% of patients in the sorafenib group and 59.3% in the non-sorafenib group (P = .405). However, the CR rate was significantly higher in the for the patients in the LDC group compared to the ones treated with SDC (73.3% vs. 33.3%, P = .002), regardless of sorafenib administration. The median time to neutrophil count recovery was 24 days for patients receiving sorafenib compared to 19.5 days for those not receiving sorafenib after Induction I (P = .0482). The median time to platelet count recovery was 16 days for the sorafenib group and 17.5 days for the non-sorafenib group (P = .0938). Sorafenib did not improve OS or EFS). Patients in the sorafenib group had a 3-year OS of 84.5% ± 5.8% compared to 69.9% ± 11.6% in the non-sorafenib group (P = .336) and a 3-year EFS of 53.1% ± 8.2% versus 54.0% ± 11.4% (P = .862). Eighty-five percent of patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) during their first complete remission (CR1), which significantly improved OS and EFS in patients with FLT3-ITD AML (P = .000). The combination of sorafenib with LDC significantly improved 3-year EFS compared to SDC (66.9% vs. 40.0%, P = .030). In multivariate analysis, sorafenib was not associated with improved outcomes in FLT3-ITD-positive pediatric AML. Conclusion: Patients with FLT3-ITD-positive AML treated with LDC with and without sorafenib achieved favorable remission. Allogeneic hematopoietic stem cell transplantation (HSCT) during first complete remission (CR1) significantly improved overall survival (OS) and event-free survival (EFS). However, sorafenib did not show a significant improvement in prognosis for pediatric patients with FLT3-ITD positive AML in this study, indicating that further randomized controlled trials may be needed to confirm its efficacy.

Atezolizumab- and bevacizumab -induced encephalitis in a patient with advanced hepatocellular carcinoma: a case report and literature review

Treatment with atezolizumab and bevacizumab is the first-line therapy for unresectable hepatocellular carcinoma. Although immune checkpoint inhibitors are novel and effective treatments, they can induce immune-related adverse events. However, neurological immune-related adverse events have rarely been reported. We report the case of a man in his 40s with hepatocellular carcinoma who developed life-threatening encephalitis after atezolizumab plus bevacizumab was administered. The patient presented with fever, headache, altered mentality, and general epileptic seizures, ten days after administration. Cerebrospinal fluid analysis showed elevated white blood cells and elevated protein levels, but revealed no infection or malignancy. Brain magnetic resonance imaging showed diffuse leptomeningeal enhancement in both the cerebrum and cerebellum. As immune checkpoint inhibitor-induced encephalitis was strongly suspected, steroid pulse therapy was initiated and neurological symptoms quickly improved. The patient was discharged after 66 days of hospitalization, and administration of sorafenib and radiotherapy was started for the hepatocellular carcinoma on an outpatient basis. This case demonstrates the importance of recognizing neurological immune-related adverse events following atezolizumab and bevacizumab treatment for early intervention. We discuss this case in comparison to available literature and previous two cases of Atezolizumab- and bevacizumab- induced encephalitis in hepatocellular carcinoma.

Co-Delivery of Tim-3 Monoclonal Antibody and Sorafenib to Enhance Chemoimmunotherapy of Liver Cancer by Using Silicon Nanosystem

In this study, mesoporous silica nanosystem (ST/SNs) was designed to co-deliver Tim-3 mAb and sorafenib (SF) for combined chemoimmunotherapy of liver cancer. The outer shell of ST/SNs is composed of Tim-3 mAb modified with metalloproteinase 2 (MMP2)-sensitive peptide, which acts as a “gating molecule” in the blood circulation to prevent drug release, and responds to Tim-3 mAb under the action of MMP2 in the tumor microenvironment Shedding enables Tim-3 mAb and SF-triggered drug release for heterotargeted cell delivery to T cells/tumor cells. In vivo tumor inhibition experiments showed that ST/SNs significantly improved tumor inhibition in tumor-bearing mice compared with sequential administration of free SF and Tim-3 mAb. At the same time, ST/SNs significantly up-regulated the expression of anti-tumor cytokines IFN-γ and IL-12 in mouse serum and the proportion of CD3+CD4+ and CD3+CD8+ cells in the tumor, showing a good immune regulation ability. In addition, at the administered dose, the blank vector exhibited low cytotoxicity and hemolysis, and no obvious hemolysis was observed. Provincial People’s Hospital. In conclusion, this study provides a promising chemoimmunotherapy combination drug combination for clinical liver cancer treatment, and provides a potential drug carrier for chemoimmunotherapy combination therapy.

Induction of the Inflammasome Pathway by Tyrosine Kinase Inhibitors Provides an Actionable Therapeutic Target for Hepatocellular Carcinoma.

During the last decade, tyrosine kinase inhibitors (TKIs) sorafenib and regorafenib have been standard systemic treatments for advanced hepatocellular carcinoma (HCC). Previous data associated sorafenib with inflammasome activation. However, the role of the inflammasome in sorafenib and regorafenib signaling has not been described in liver cancer patients. For this purpose, we analyzed inflammasome-related transcriptomic changes in a murine HCC model. Our data confirmed inflammasome activation after both TKI treatments, sharing a similar pattern of increased gene expression. According to human database results, transcriptional increase of inflammasome genes is associated with poorer prognosis for male liver cancer patients, suggesting a sex-dependent role for inflammasome activation in HCC therapy. In biopsies of HCC and its surrounding tissue, we detected durable increases in the inflammasome activation pattern after sorafenib or regorafenib treatment in male patients. Further supporting its involvement in sorafenib action, inflammasome inhibition (MCC950) enhanced sorafenib anticancer activity in experimental HCC models, while no direct in vitro effect was observed in HCC cell lines. Moreover, activated human THP-1 macrophages released IL-1β after sorafenib administration, while 3D Hep3B spheres displayed increased tumor growth after IL-1β addition, pointing to the liver microenvironment as a key player in inflammasome action. In summary, our results unveil the inflammasome pathway as an actionable target in sorafenib or regorafenib therapy and associate an inflammasome signature in HCC and surrounding tissue with TKI administration. Therefore, targeting inflammasome activation, principally in male patients, could help to overcome sorafenib or regorafenib resistance and enhance the efficacy of TKI treatments in HCC.

Adjuvant Transarterial Chemoembolization With Sorafenib for Portal Vein Tumor Thrombus

Certain patients with hepatocellular carcinoma with portal vein tumor thrombus could benefit from surgical resection, and postoperative adjuvant therapy may lower the incidence of tumor recurrence. To compare the efficacy and safety of sorafenib plus transarterial chemoembolization vs sorafenib alone as postoperative adjuvant therapy for patients with hepatocellular carcinoma with portal vein tumor thrombus. This was a phase 3, multicenter, randomized clinical trial conducted in 5 hospitals in China. A total of 158 patients were enrolled and randomized from October 2019 to March 2022, with a median follow-up of 28.4 months. Portal vein tumor thrombus was graded by the Cheng classification. Eligible patients with hepatocellular carcinoma with Cheng grade I to III portal vein tumor thrombus (ie, involving segmental or sectoral branches, right- or left-side branch, or main trunk of portal vein) were included. Patients were randomly assigned 1:1 to receive transarterial chemoembolization with sorafenib or sorafenib alone as postoperative adjuvant therapy. Sorafenib treatment was started within 3 days after randomization, with an initial dose of 400 mg orally twice a day. In the transarterial chemoembolization with sorafenib group, transarterial chemoembolization was performed 1 day after the first administration of sorafenib. The primary end point was recurrence-free survival. Efficacy was assessed in the intention-to-treat population and safety was assessed in patients who received at least 1 dose of study treatment. Of 158 patients included, the median (IQR) age was 54 (43-61) years, and 140 (88.6%) patients were male. The median (IQR) recurrence-free survival was significantly longer in the transarterial chemoembolization with sorafenib group (16.8 [12.0-NA] vs 12.6 [7.8-18.1] months; hazard ratio [HR], 0.57; 95% CI, 0.39-0.83; P = .002). The median (IQR) overall survival was also significantly longer with transarterial chemoembolization with sorafenib than with sorafenib alone (30.4 [20.6-NA] vs 22.5 [15.4-NA] months; HR, 0.57; 95% CI, 0.36-0.91; P = .02). The most common grade 3/4 adverse event was hand-foot syndrome (23 of 79 patients in the transarterial chemoembolization with sorafenib group [29.1%] vs 24 of 79 patients in the sorafenib alone group [30.4%]). There were no treatment-related deaths in either group. The transarterial chemoembolization with sorafenib group did not show additional toxicity compared with the sorafenib monotherapy group. In this study, the combination of sorafenib and transarterial chemoembolization as postoperative adjuvant therapy in patients with hepatocellular carcinoma with portal vein tumor thrombus resulted in longer recurrence-free survival and overall survival than sorafenib alone and was well tolerated. ClinicalTrials.gov Identifier: NCT04143191.

Sorafenib reduces the production of epoxyeicosatrienoic acids and leads to cardiac injury by inhibiting CYP2J in rats

Sorafenib, an important cancer drug in clinical practice, has caused heart problems such as hypertension, myocardial infarction, and thrombosis. Although some mechanisms of sorafenib-induced cardiotoxicity have been proposed, there is still more research needed to reach a well-established definition of the causes of cardiotoxicity of sorafenib. In this report, we demonstrate that sorafenib is a potent inhibitor of the CYP2J enzyme. Sorafenib significantly inhibited the production of epoxyeicosatrienoic acids (EETs) in rat cardiac microsomes. The in vivo experimental results also showed that after the administration of sorafenib, the levels of 11,12-EET and 14,15-EET in rat plasma were significantly reduced, which was similar to the results of CYP2J gene knockout. Sorafenib decreased the levels of EETs, leading to abnormal expression of mitochondrial fusion and fission factors in heart tissue. In addition, the expression of mitochondrial energy metabolism factors (Pgc-1α, Pgc-1β, Ampk, and Sirt1) and cardiac mechanism factors (Scn5a and Prkag2) was significantly reduced, increasing the risk of arrhythmia and heart failure. Meanwhile, the increase in injury markers Anp, CK, and CK-MB further confirmed the cardiotoxicity of sorafenib. This study is of great significance for understanding the cardiotoxicity of sorafenib, and is also a model for studying the cardiotoxicity of other drugs that inhibit CYP2J activity.

Clinicopathological Aspects and Inflammation-Immune Markers in Alcohol and/or Hepatitis C Virus-Induced Hepatocellular Carcinoma Patients Treated With Sorafenib.

Tyrosine kinase inhibitors have been used to treat hepatocellular carcinoma (HCC), but the outcomes of patients under treatment vary. Since the roles of clinicopathological aspects and markers of chronic inflammation/immune homeostasis in the outcome of HCC patients treated with sorafenib are still unclear, these were the aims of this study. Patients with alcohol-induced and/or hepatitis C virus (HCV)-induced HCC (n = 182) uniformly treated with sorafenib were included in the study. Baseline clinicopathological aspects of patients were computed from the medical records. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic inflammation response index (SIRI), and systemic immune-inflammation index (SII) were obtained from the hematological exam performed before the administration of sorafenib. Overall survival (OS) was analyzed using Kaplan-Meier probabilities, log-rank test, and univariate and multivariate Cox proportional hazard ratio (HR) analyses. In multivariate analysis, alpha-foetoprotein (AFP) level and Child-Pugh score were predictors of OS. Patients with AFP levels higher than 157 ng/mL and Child-Pugh B or C had 1.40 (95% confidence interval (CI): 1.03 - 1.91, P = 0.03) and 1.64 (95% CI: 1.07 - 2.52, P = 0.02) more chances of evolving to death than the remaining patients, respectively. NLR, PLR, LMR, SIRI, and SII did not alter the OS of HCC patients. AFP level and Child-Pugh score act as independent prognostic factors in patients with alcohol and/or HCV-induced HCC treated with sorafenib, but markers of chronic inflammation/immune homeostasis seem not to alter the outcome of patients with HCC induced by alcohol and/or HCV.

MRI radiomics to monitor therapeutic outcome of sorafenib plus IHA transcatheter NK cell combination therapy in hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is a common liver malignancy with limited treatment options. Previous studies expressed the potential synergy of sorafenib and NK cell immunotherapy as a promising approach against HCC. MRI is commonly used to assess response of HCC to therapy. However, traditional MRI-based metrics for treatment efficacy are inadequate for capturing complex changes in the tumor microenvironment, especially with immunotherapy. In this study, we investigated potent MRI radiomics analysis to non-invasively assess early responses to combined sorafenib and NK cell therapy in a HCC rat model, aiming to predict multiple treatment outcomes and optimize HCC treatment evaluations.MethodsSprague Dawley (SD) rats underwent tumor implantation with the N1-S1 cell line. Tumor progression and treatment efficacy were assessed using MRI following NK cell immunotherapy and sorafenib administration. Radiomics features were extracted, processed, and selected from both T1w and T2w MRI images. The quantitative models were developed to predict treatment outcomes and their performances were evaluated with area under the receiver operating characteristic (AUROC) curve. Additionally, multivariable linear regression models were constructed to determine the correlation between MRI radiomics and histology, aiming for a noninvasive evaluation of tumor biomarkers. These models were evaluated using root-mean-squared-error (RMSE) and the Spearman correlation coefficient.ResultsA total of 743 radiomics features were extracted from T1w and T2w MRI data separately. Subsequently, a feature selection process was conducted to identify a subset of five features for modeling. For therapeutic prediction, four classification models were developed. Support vector machine (SVM) model, utilizing combined T1w + T2w MRI data, achieved 96% accuracy and an AUROC of 1.00 in differentiating the control and treatment groups. For multi-class treatment outcome prediction, Linear regression model attained 85% accuracy and an AUC of 0.93. Histological analysis showed that combination therapy of NK cell and sorafenib had the lowest tumor cell viability and the highest NK cell activity. Correlation analyses between MRI features and histological biomarkers indicated robust relationships (r = 0.94).ConclusionsOur study underscored the significant potential of texture-based MRI imaging features in the early assessment of multiple HCC treatment outcomes.

MRI monitoring of combined therapy with transcatheter arterial delivery of NK cells and systemic administration of sorafenib for the treatment of HCC.

This preclinical study explored the synergistic potential of sorafenib and NK cell chemoimmunotherapy to combat hepatocellular carcinoma (HCC) in a rat model. We aimed to enhance NK cell cytotoxicity through IL-12/18 cytokines supplementation and elucidate the underlying molecular mechanisms driving this collaborative antitumor action. Twenty-four Sprague-Dawley rats were divided into distinct treatment groups, receiving sorafenib via gavage and NK cells via catheterization of the proper hepatic artery. Tumor growth and treatment response were monitored through weekly MRI scans, including T1w, T2w, DCE, and DWI sequences. Histological examinations assessed tumor cell viability, apoptosis fraction, and microvessel density. The combined therapy demonstrated significant inhibition of tumor growth, angiogenesis, and induction of durable antitumor immunity compared to either modality alone. DCE-MRI and DWI revealed distinct alterations in tumor microvasculature, highlighting the effectiveness of the combination. Our findings highlight the promise of sorafenib-augmented NK cell chemoimmunotherapy as a potential therapeutic strategy for HCC management. The targeted delivery of IL-12/18 cytokines supplemented NK cells effectively enhanced cytotoxicity within the tumor microenvironment, leading to improved antitumor responses. Further investigation in clinical trials is warranted to validate these findings in human patients and explore the translational potential of this approach.

Actual issues of secondary prevention of liver cancer in Kazakhstan

Liver cancer is characterized by high mortality and low survival rates in most countries of the world. According to the WHO data, more than 1.3 million people with liver cancer die annually in the world and according to the data of the 9th volume of "Cancer on five continents" - the highest standardized incidence rates are in Korea - 44.9 per 100 thousand population as well as in Thailand, Japan, China. Low rates were in Algeria, India, Belgium and the Netherlands. In Russia 61.5% of patients die of liver cancer progression in the first year after diagnosis [1,2].<br /> Information on the global burden of cancer in 2018 showed that the specific weight of liver cancer in the structure of malignant neoplasms (MN) is 8.2%, and in 2020 - 8.3% [3].  <br /> The worldwide peculiarity of liver cancer is its late diagnosis. Several evidence-based treatment options for liver cancer are currently available: liver transplantation for hepatocellular liver cancer (HCC) (according to the Milan criteria), radiofrequency ablation as a radical treatment option (RFA), chemoembolization for intrahepatic cholangiocarcinoma (TACE), and the administration of Sorafenib as systemic therapy [4].<br /> Current approaches for the treatment of early-stage primary liver cancer are represented by hepatic RFA, and the efficacy of this approach depends on the subjective attentiveness and visual acuity of the clinician. The latest technique used in liver RFA is the hyperspectral imaging which utilize objective assessment [2].<br /> Ultrasound is usually used to detect liver lesions, but the detection rate is low for many reasons, such as clinician skills and technical capabilities. Modern approaches of diagnostic capabilities, such as contrast-enhanced ultrasound integrated imaging (CEUS) and comprehensive ultrasound imaging - contrast-enhanced CT (CECT) or contrast-enhanced MRI (CEMRI) for visualization of focal liver lesions (FLL) - increase the confidence of the interventional physician so it should be recommended for use as a routine procedure [5-6].<br /> The ratio of morbidity and mortality in many countries reaches 91.6%, which represents the third most important cause of cancer deaths [7-9].

Bioengineered DNA-decorated UiO-66-based nanocarriers for combined administration of doxorubicin and sorafenib: Hepatocellular carcinoma treatment and chemotherapy

Natural biomaterials were used to decorate UiO-66-NH2 to develop a platform for co-drug delivery of doxorubicin and sorafenib as a cost-effective and easy way to use a drug delivery system (DDS). To properly characterize the modified MOFs, standard analytical methods were used. Then doxorubicin and sorafenib were loaded into and onto the porosity of the MOF, UiO-66-NH2. The surface morphological analysis, FESEM, and TEM images revealed the hexagonal structure of the UiO-66-NH2, demonstrating the successful synthesis of these green MOFs. Internalization and loading of doxorubicin on the MCF-7 cell line was investigated with two-dimensional fluorescence microscopy, which shows that drug internalizations on the cancerous cells were successful and promising. The drug payload of 49.5% and 31.2% for doxorubicin and sorafenib were attained, respectively. Study on the MCF-7 HT-29 and HEK-293 cell lines exhibited excellent cell viability when subjected to both low and high concentrations of 0.1 µg.mL−1 and 50 µg.mL−1, respectively. After 24 h of treatment, the relative cell viability of 85.1%, 88.1%, and 76.8% was achieved for the HT-29, HEK-293, and MCF-7 cell lines, respectively. In addition, after 48 h of treatment, the relative cell viability of 82.5%, 83.5%, and 68.5% was recorded, respectively. However, the percentage of cell viability was dramatically reduced by coating the nanocarrier with Ginkgo biloba leaf extract and E. Coli DNA (62.6%, 40.9%, and 45.1% for 24 h treatment and 62.1%, 38.5%, and 38.9% for 48 h treatment in HEK-293, HT-29, and MCF-7 cell lines, respectively).

SNHG1, interacting with SND1, contributes to sorafenib resistance of liver cancer cells by increasing m6A-mediated SLC7A11 expression and promoting aerobic glycolysis.

Aerobic glycolysis plays an important role in multidrug resistance of cancer cells. Here, we screened different expressed lncRNAs associated with sorafenib resistance of liver cancer cells, by intersecting the bioinformatics analyses of TCGA and GEO (the GSE62813 dataset) databases. Our results revealed that the 18 upregulated lncRNAs in the intersection are associated with and enriched in metabolism of small molecule organic acids, suggesting their potential in glycolysis. The lncRNA small nucleolar RNA host gene 1 (Snhg1) was chosen as a potential regulator of aerobic glycolysis in liver cancer cells, for its significant promotion on lactate production. Gain- and loss-of-function experiments mediated by Crispr-Cas9 technique in HepG2 cells indicated that Snhg1 promoted cell proliferation, invasion, sorafenib resistance, and aerobic glycolysis. In the mechanism exploration, we found that Snhg1 can interact with SND1 protein, a famous RNA binding protein and recently identified "Reader" of N6-methyladenosine (m6A). SND1 was demonstrated to be positively regulated by Snhg1 and had similar promoting effects on proliferation, invasion, sorafenib resistance, and aerobic glycolysis of HepG2 cells. SND1 bound with and promoted the expression of SLC7A11, an aerobic glycolysis regulator. Furthermore, either silencing SLC7A11 or blocking aerobic glycolysis with 2-deoxy-d-glucose (2-DG) was able to reverse the promotion of Snhg1 overexpression on malignancy, sorafenib resistance, and aerobic glycolysis of HepG2 cells. Finally, in a liver cancer xenograft mouse model, we found that formed tumors with Snhg1-knocked-down HepG2 cells were more sensitive to sorafenib administration. Altogether, SNHG1 contributes to sorafenib resistance of liver cancer cells by promoting SND1-m6A-SLC7A11-mediated aerobic glycolysis.

Simultaneous quantification of donafenib, sorafenib, and their N-oxide metabolites in rat plasma using a HPLC-MS/MS method

Donafenib and sorafenib are small molecule chemotherapy drugs for the management of hepatocellular carcinoma, with donafenib being a deuterated derivative of sorafenib. To date, a high liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method that quantify donafenib, sorafenib, and their main metabolites has not yet been developed. The objective of this study was to establish a HPLC-MS/MS method for the simultaneous detection of donafenib, donafenib-N-oxide, sorafenib, and sorafenib-N-oxide and for the pharmacokinetic studies in rat. The extraction of all analytes was achieved by simple protein precipitation utilizing acetonitrile. The Waters XBridge C18 column (2.1 × 100 mm, 3.5 µm) was selected, and the analytes could be efficiently separated and quantitated during a 2.8 min gradient elution procedure. The method was linear within the predefined quantification ranges and provided acceptable precision (%CV < 9.4%), reproducible extraction recovery (99.4%–111.5%), and low matrix effect (88.1%–98.6%). The hemolysis effect did not interfere with the quantification of all analytes, and similar results were obtained by changing the anticoagulant K2-EDTA to heparin or sodium citrate. Plasma pharmacokinetics revealed that the values of t1/2, Cmax, and AUC0-t of donafenib were 1.4-, 6.2-, and 3.1-fold higher than those of sorafenib, respectively. In conclusion, the proposed bioassay was successfully applied to pharmacokinetic studies in rat after administration of donafenib and sorafenib. Our work not only improves the bioanalytical method for determining the plasma concentrations of donafenib, sorafenib, and their N-oxide metabolites, but also provides a scientific reference for clinical pharmacokinetic studies.

P53 and VEGF are promising biomarkers for sorafenib efficacy in an experimental model of NASH-related HCC.

The efficacy of systemic therapy for hepatocellular carcinoma (HCC) related to non-alcoholic steatohepatitis (NASH) is poorly understood. In this study we evaluated the effects of sorafenib based on the expression of molecular markers related to major hepatocarcinogenesis pathways and angiogenesis in a NASH-related HCC model. Forty male rats were submitted to NASH-HCC induction through the combination of a high-fat and choline deficient diet and diethylnitrosamine (100mg/L) administration in the drinking water for 13 and 16weeks. After the induction period, the rats received daily gavage administration of saline solution (control) or Sorafenib (5mg/kg/day) for 3weeks. Thereafter, the animals were euthanized and samples from liver nodules were collected for histopathological analysis and immunohistochemical assessment of HEP-PAR-1, glutamine-synthetase, VEGF, survivin, β-catenin and p53. A semi-quantitative score was used for VEGF, survivin and β-catenin analysis. For p53, the percentage of positive cells was determined. Results were processed by Wilcoxon's test or Student's t-test. Both protocols efficiently induced HCC, most of them being moderately to poorly differentiated. Sorafenib-treated animals showed a decreased expression of VEGF and p53 in HCCs generated at 13weeks when compared to control animals (p = 0.03; p = 0.04, respectively). No significant difference in β-catenin and survivin were observed. There was a significant decrease in VEGF and p53 expression when comparing the two control groups (13 vs. 16weeks, p < 0.01). p53 and VEGF are promising biomarkers for assessment of efficacy of Sorafenib, whereas survivin and β-catenin were not found useful. Decreased immunohistochemical expression of p53 and VEGF in the 16week control group may indicate a different metabolic status of HCC.

Portal hemodynamic effects of different TKIs in patients with advanced hepatocellular carcinoma: A prospective cohort study.

e15126 Background: Tyrosine kinase inhibitors (TKIs) are considered to have effects on portal collateral circulation with portal hypertension. According to previous small sample clinical reports, short-term administration of sorafenib might have an effect of decreasing portal venous pressure, while lenvatinib aggravated portal hypertension. Long-term effects of TKIs on portal pressure are still unclear. Therefore, We conducted a prospective cohort study to explore the efficacy of different TKIs for portal circulation in patients with advanced hepatocellular carcinoma. Methods: 27 Child-Pugh class A or B patients with advanced HCC were enrolled in this study, 13 patients received lenvatinib, 7 patients sorafenib, and 7 patients regorafenib. Changes of portal hemodynamic parameters were measured by duplex Doppler ultrasonography, including portal venous area (PVA), portal venous flow velocity (PVV) and congestion index (CI) before and after administration of TKIs for an average 40-50 days. Results: In both regorafenib and sorafenib cohorts, PVA decreased after treatment, although the difference was not significant. PVF significantly reduced in sorafenib cohort (24.96±5.60 vs. 15.46±4.50, P= 0.014) and regorafenib cohort (21.43±2.09 vs. 16.01±1.28, P= 0.024), therefore CI significantly increased in sorafenib cohort (0.060±0.042 vs. 0.088±0.040, P= 0.046) and regorafenib cohort (0.068±0.032 vs. 0.090±0.030, P= 0.043). In lenvatinib, both PVA and PVF have no significant change, while CI increased significantly (0.057±0.027 vs. 0.074±0.040, P= 0.030). Conclusions: In this study, TKIs showed different effects on portal hemodynamic change in advanced HCC. Large sample and long time follow-up research will be necessary to verify their clinical and mechanism effects. [Table: see text]

Transmembrane protein 147, as a potential Sorafenib target, could expedite cell cycle process and confer adverse prognosis in hepatocellular carcinoma.

TMEM147 was identified as a core component of ribosome-bound translocon complex at ER/NE. So far, sparse studies reported its expression profiling and oncological implications in hepatocellular carcinoma (HCC) patients. Here we inspected TMEM147 expression levels in HCC cohorts from public databases and tumor tissues. TMEM147 was augmented at transcriptional levels (p < 0.001) and protein levels in HCC patients. A series of bioinformatics tools implemented in R studio were orchestrated in TCGA-LIHC to evaluate the prognostic significance, compile relevant gene clusters, and explore the oncological functions and therapy responses. It is suggested that TMEM147 could predict poor clinical outcomes effectively and independently (p < 0.001, HR = 2.231 for overall survival (OS) vs. p = 0.04, HR = 2.296 for disease-specific survival), and was related to risk factors including advanced histologic tumor grade (p < 0.001), AFP level (p < 0.001) and vascular invasion (p = 0.007). Functional enrichment analyses indicated that TMEM147 was involved in cell cycle, WNT/MAPK signaling pathways and ferroptosis. Expression profiling in HCC cell lines, mouse model, and a clinical trial revealed that TMEM147 was a considerable target and marker for adjuvant therapy in vitro and in vivo. Subsequentially, in vitro wet-lab experimentation authenticated that TMEM147 would be downregulated by Sorafenib administration in hepatoma cells. Lentivirus-mediated overexpression of TMEM147 could promote cell cycle progression from S phase into G2/M phase, and enhance cell proliferation, thus attenuating drug efficacy and sensitivity of Sorafenib. Further explorations into TMEM147 may inspire a fresh perspective to predict clinical outcomes and improve therapeutic efficacy for HCC patients.

Tolerance of sorafenib in patients with residual HCC post TACE

Background: Hepatocellular carcinoma (HCC) is among the most prevalent cancers and the second leading cause of cancer-related mortality globally. Objective: The aim was to investigate the sensitivity of sorafenib administration after TACE in advanced HCC patients. Methods: From June 2021 to June 2022, 36 patients from Hayatabad Medical Complex Peshawar were enrolled in this retrospective research. Based on the correct state of liver activity, sorafenib medication was started within two weeks of finishing TACE treatment. Throughout each follow-up, the liver and kidney function, adverse effects, and medicinal impact were assessed using the Modified response assessment criteria in solid tumors (mRECIST). Results: The mean overall survival (mOS) and mean time to progress (mTTP) were 11.5 months and 7.5 months, respectively. Patients with one or more localised hepatic lesions were respectively 18 months and 12 months old (2 = 4.613, P = 0.0314). No patients had a full response, three had partial responses, 11 had stable disease (SD), and 22 had progressive illness (PD), as per the mRECIST. The disease control rate (DCR) was 38.89% (14/36) and the response rate was 8.33% (3/36) for both. Hand-foot skin irritation (21 incidences, 58.3%), and diarrhoea (17 incidences, 47.22%) were the predominant adverse effects.

Adjuvant transarterial chemoembolization with sorafenib for patients with hepatocellular carcinoma with portal vein tumor thrombus after surgery: A phase III, multicenter, randomized, controlled trial.

493 Background: To compare the efficacy and safety of sorafenib plus transarterial chemoembolization (SOR-TACE) versus sorafenib alone as postoperative adjuvant therapy for hepatocellular carcinoma (HCC) patients with portal vein thrombus (PVTT). Methods: This was a phase III, multicenter, randomized, control clinical trial. Eligible HCC patients with PVTT were included and randomly assigned (1:1) to receive SOR-TACE or sorafenib alone as postoperative adjuvant therapy. Sorafenib treatment was started within 3 days after randomization, with an initial dose of 400mg twice a day. In the SOR-TACE group, TACE was performed one day after the administration of sorafenib. The primary endpoint was recurrence-free survival (RFS). Results: From October 2019 to March 2022, a total of 158 HCC patients with PVTT from China were enrolled and randomized. After a median follow-up duration of 28.4 months, the median RFS was significantly longer in the SOR-TACE group (16.8 vs. 12.6 months; hazard ratio, 0.57; P = 0.002). The median overall survival (OS) was also significantly longer with SOR-TACE than with sorafenib (30.4 vs. 22.5 months; hazard ratio, 0.57; P = 0.017). Multivariable analysis indicated SOR-TACE treatment was an independent risk factor for both RFS and OS. The SOR-TACE group did not show additional toxicity compared with the sorafenib alone group. Conclusions: The combination of sorafenib and TACE as postoperative adjuvant therapy in HCC patients with PVTT resulted in longer RFS and OS compared to sorafenib alone and was well tolerated. Clinical trial information: NCT04143191 .

Differential in vitro effects of targeted therapeutics in primary human liver cancer: importance for combined liver cancer

The incidence of primary liver tumors, hepatocellular carcinoma (HCC), intrahepatic cholangiocellular carcinoma (ICC), and combined HCC/ICC (cHCC/CC) is increasing. For ICC, targeted therapy exists only for a small subpopulation of patients, while for HCC, Sorafenib and Lenvatinib are in use. Diagnosis of cHCC/CC is a great challenge and its incidence is underestimated, bearing the risk of unintended non-treatment of ICC. Here, we investigated effects of targeted inhibitors on human ICC cell lines (HUH28, RBE, SSP25), in comparison to extrahepatic (E)CC lines (EGI1, CCC5, TFK1), and HCC/hepatoblastoma cell lines (HEP3B, HUH7, HEPG2). Cells were challenged with: AKT inhibitor MK-2206; multikinase inhibitors Sorafenib, Lenvatinib and Dasatinib; PI3-kinase inhibitors BKM-120, Wortmannin, LY294002, and CAL-101; and mTOR inhibitor Rapamycin. Dosage of the substances was based on the large number of published data of recent years. Proliferation was analyzed daily for four days. All cell lines were highly responsive to MK-2206. Thereby, MK-2206 reduced expression of phospho(p)-AKT in all ICC, ECC, and HCC lines, which mostly corresponded to reduction of p-mTOR, whereas p-ERK1/2 was upregulated in many cases. Lenvatinib showed inhibitory effects on the two HCC cell lines, but not on HEPG2, ICCs and ECCs. Sorafenib inhibited proliferation of all cells, except the ECC line CCC5. However, at reduced dosage, we observed increased cell numbers in some ICC experiments. Dasatinib was highly effective especially in ICC cell lines. Inhibitory effects were observed with all four PI3-kinase inhibitors. However, cell type-specific differences were also evident here. Rapamycin was most effective in the two HCC cell lines. Our studies show that the nine inhibitors differentially target ICC, ECC, and HCC/hepatoblastoma lines. Caution should be taken with Lenvatinib and Sorafenib administration in patients with cHCC/CC as the drugs may have no effects on, or might even stimulate, ICC.