Tislelizumab versus sorafenib as first-line treatment for advanced hepatocellular carcinoma in China: a cost-effectiveness analysis.

Objective: The goal of this study is to compare the cost-effectiveness of tislelizumab and sorafenib as first-line treatment for advanced hepatocellular carcinoma in China. Methods: A comprehensive cost-effectiveness analysis was undertaken within the framework of a partitioned survival model to accurately gage the incremental cost-effectiveness ratio (ICER) of tislelizumab compared to sorafenib. The model incorporated relevant clinical data and all survival rates were from RATIONALE-301 trials. The stability of the partitioned survival model was assessed by performing one-way and two-way sensitivity analyses. Results: The total cost incurred for the tislelizumab treatment was $16181.24, whereas the sorafenib was $14306.87. The tislelizumab regimen resulted in a significant increase of 0.18 quality-adjusted life years (QALYs) and an extra cost of $1874.37 as compared to chemotherapy. The ICER was $10413.17 per QALY, which was found to be below the willingness-to-pay (WTP) threshold of $37304.34/QALY. The results of the sensitivity analysis found that no fluctuations in any of the factors affected our results, even when these parameters fluctuated. Conclusion: Tislelizumab appears to be a cost-effective first-line treatment for advanced hepatocellular carcinoma when compared to sorafenib in China. These findings can inform decision-making processes regarding the selection of the most cost-effective treatment option for advanced hepatocellular carcinoma.

Loss of lncRNA LINC01056 leads to sorafenib resistance in HCC.

BACKGROUND AND AIMS: Sorafenib is a major nonsurgical option for patients with advanced hepatocellular carcinoma (HCC); however, its clinical efficacy is largely undermined by the acquisition of resistance. The aim of this study was to identify the key lncRNA involved in the regulation of the sorafenib response in HCC. MATERIALS AND METHODS: A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) single-guide RNA (sgRNA) synergistic activation mediator (SAM)-pooled lncRNA library was applied to screen for the key lncRNA regulated by sorafenib treatment. The role of the identified lncRNA in mediating the sorafenib response in HCC was examined in vitro and in vivo. The underlying mechanism was delineated by proteomic analysis. The clinical significance of the expression of the identified lncRNA was evaluated by multiplex immunostaining on a human HCC microtissue array. RESULTS: CRISPR/Cas9 lncRNA library screening revealed that Linc01056 was among the most downregulated lncRNAs in sorafenib-resistant HCC cells. Knockdown of Linc01056 reduced the sensitivity of HCC cells to sorafenib, suppressing apoptosis in vitro and promoting tumour growth in mice in vivo. Proteomic analysis revealed that Linc01056 knockdown in sorafenib-treated HCC cells induced genes related to fatty acid oxidation (FAO) while repressing glycolysis-associated genes, leading to a metabolic switch favouring higher intracellular energy production. FAO inhibition in HCC cells with Linc01056 knockdown significantly restored sensitivity to sorafenib. Mechanistically, we determined that PPARα is the critical molecule governing the metabolic switch upon Linc01056 knockdown in HCC cells and indeed, PPARα inhibition restored the sorafenib response in HCC cells in vitro and HCC tumours in vivo. Clinically, Linc01056 expression predicted optimal overall and progression-free survival outcomes in HCC patients and predicted a better sorafenib response. Linc01056 expression indicated a low FAO level in HCC. CONCLUSION: Our study identified Linc01056 as a critical epigenetic regulator and potential therapeutic target in the regulation of the sorafenib response in HCC.

Dihydroartemisinin induces ferroptosis of hepatocellular carcinoma via inhibiting ATF4-xCT pathway.

Management of hepatocellular carcinoma (HCC) remains challenging due to population growth, frequent recurrence and drug resistance. Targeting of genes involved with the ferroptosis is a promising alternative treatment strategy for HCC. The present study aimed to investigate the effect of dihydroartemisinin (DHA) against HCC and explore the underlying mechanisms. The effects of DHA on induction of ferroptosis were investigated with the measurement of malondialdehyde concentrations, oxidised C11 BODIPY 581/591 staining, as well as subcutaneous xenograft experiments. Activated transcription factor 4 (ATF4) and solute carrier family 7 member 11 (SLC7A11 or xCT) were overexpressed with lentiviruses to verify the target of DHA. Here, we confirmed the anticancer effect of DHA in inducing ferroptosis is related to ATF4. High expression of ATF4 is related to worse clinicopathological prognosis of HCC. Mechanistically, DHA inhibited the expression of ATF4, thereby promoting lipid peroxidation and ferroptosis of HCC cells. Overexpression of ATF4 rescued DHA-induced ferroptosis. Moreover, ATF4 could directly bound to the SLC7A11 promoter and increase its transcription. In addition, DHA enhances the chemosensitivity of sorafenib on HCC in vivo and in vitro. These findings confirm that DHA induces ferroptosis of HCC via inhibiting ATF4-xCT pathway, thereby providing new drug options for the treatment of HCC.

IL-22 signaling promotes sorafenib resistance in hepatocellular carcinoma via STAT3/CD155 signaling axis.

Introduction: Sorafenib is currently the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Nevertheless, sorafenib resistance remains a huge challenge in the clinic. Therefore, it is urgent to elucidate the mechanisms underlying sorafenib resistance for developing novel treatment strategies for advanced HCC. In this study, we aimed to investigate the role and mechanisms of interleukin-22 (IL-22) in sorafenib resistance in HCC. Methods: The in vitro experiments using HCC cell lines and in vivo studies with a nude mouse model were used. Calcium staining, chromatin immunoprecipitation, lactate dehydrogenase release and luciferase reporter assays were employed to explore the expression and roles of IL-22, STAT3 and CD155 in sorafenib resistance. Results: Our clinical results demonstrated a significant correlation between elevated IL-22 expression and poor prognosis in HCC. Analysis of transcriptomic data from the phase-3 STORM-trial (BIOSTORM) suggested that STAT3 signaling activation and natural killer (NK) cell infiltration may associate sorafenib responses. STAT3 signaling could be activated by IL-22 administration in HCC cells, and then enhanced sorafenib resistance in HCC cells by promoting cell proliferation and reducing apoptosis in vitro and in vivo. Further, we found IL-22/STAT3 axis can transcriptionally upregulate CD155 expression in HCC cells, which could significantly reduce NK cell-mediated HCC cell lysis in a co-culture system. Conclusions: Collectively, IL-22 could contribute to sorafenib resistance in HCC by activating STAT3/CD155 signaling axis to decrease the sensitivities of tumor cells to sorafenib-mediated direct cytotoxicity and NK cell-mediated lysis. These findings deepen the understanding of how sorafenib resistance develops in HCC in terms of IL-22/STAT3 signaling pathway, and provide potential targets to overcome sorafenib resistance in patients with advanced HCC.

Assessment of disease control rate and safety of sorafenib in targeted therapy for advanced liver cancer.

OBJECTIVE: The clinical efficacy and safety of sorafenib in patients with advanced liver cancer (ALC) were evaluated based on transarterial chemoembolization (TACE). METHODS: 92 patients with ALC admitted to our hospital from May 2020 to August 2022 were randomly rolled into a control (Ctrl) group and an observation (Obs) group, with 46 patients in each. Patients in the Ctrl group received TACE treatment, while those in the Obs group received sorafenib molecular targeted therapy (SMTT) on the basis of the treatment strategy in the Ctrl group (400 mg/dose, twice daily, followed by a 4-week follow-up observation). Clinical efficacy, disease control rate (DCR), survival time (ST), immune indicators (CD3+, CD4+, CD4+/CD8+), and adverse reactions (ARs) (including mild fatigue, liver pain, hand-foot syndrome (HFS), diarrhea, and fever) were compared for patients in different groups after different treatments. RESULTS: the DCR in the Obs group (90%) was greatly higher to that in the Ctrl group (78%), showing an obvious difference (P < 0.05). The median ST in the Obs group was obviously longer and the median disease progression time (DPT) was shorter, exhibiting great differences with those in the Ctrl group (P < 0.05). Moreover, no great difference was observed in laboratory indicators between patients in various groups (P > 0.05). After treatment, the Obs group exhibited better levels in all indicators. Furthermore, the incidence of ARs in the Obs group was lower and exhibited a sharp difference with that in the Ctrl group (P < 0.05). CONCLUSION: SMTT had demonstrated good efficacy in patients with ALC, improving the DCR, enhancing the immune response of the body, and reducing the incidence of ARs, thereby promoting the disease outcome. Therefore, it was a treatment method worthy of promotion and application.

Efficacy of radiofrequency ablation combined with sorafenib for treating liver cancer complicated with portal hypertension and prognostic factors.

BACKGROUND: Patients with liver cancer complicated by portal hypertension present complex challenges in treatment. AIM: To evaluate the efficacy of radiofrequency ablation in combination with sorafenib for improving liver function and its impact on the prognosis of patients with this condition. METHODS: Data from 100 patients with liver cancer complicated with portal hypertension from May 2014 to March 2019 were analyzed and divided into a study group (n = 50) and a control group (n = 50) according to the treatment regimen. The research group received radiofrequency ablation (RFA) in combination with sorafenib, and the control group only received RFA. The short-term efficacy of both the research and control groups was observed. Liver function and portal hypertension were compared before and after treatment. Alpha-fetoprotein (AFP), glypican-3 (GPC-3), and AFP-L3 levels were compared between the two groups prior to and after treatment. The occurrence of adverse reactions in both groups was observed. The 3-year survival rate was compared between the two groups. Basic data were compared between the survival and non-surviving groups. To identify the independent risk factors for poor prognosis in patients with liver cancer complicated by portal hypertension, multivariate logistic regression analysis was employed. RESULTS: When comparing the two groups, the research group's total effective rate (82.00%) was significantly greater than that of the control group (56.00%; P < 0.05). Following treatment, alanine aminotransferase and aspartate aminotransferase levels increased, and portal vein pressure decreased in both groups. The degree of improvement for every index was substantially greater in the research group than in the control group (P < 0.05). Following treatment, the AFP, GPC-3, and AFP-L3 levels in both groups decreased, with the research group having significantly lower levels than the control group (P < 0.05). The incidence of diarrhea, rash, nausea and vomiting, and fatigue in the research group was significantly greater than that in the control group (P < 0.05). The 1-, 2-, and 3-year survival rates of the research group (94.00%, 84.00%, and 72.00%, respectively) were significantly greater than those of the control group (80.00%, 64.00%, and 40.00%, respectively; P < 0.05). Significant differences were observed between the survival group and the non-surviving group in terms of Child-Pugh grade, history of hepatitis, number of tumors, tumor size, use of sorafenib, stage of liver cancer, histological differentiation, history of splenectomy and other basic data (P < 0.05). Logistic regression analysis demonstrated that high Child-Pugh grade, tumor size (6-10 cm), history of hepatitis, no use of sorafenib, liver cancer stage IIIC, and previous splenectomy were independent risk factors for poor prognosis in patients with liver cancer complicated with portal hypertension (P < 0.05). CONCLUSION: Patients suffering from liver cancer complicated by portal hypertension benefit from the combination of RFA and sorafenib therapy because it effectively restores liver function and increases survival rates. The prognosis of patients suffering from liver cancer complicated by portal hypertension is strongly associated with factors such as high Child-Pugh grade, tumor size (6-10 cm), history of hepatitis, lack of sorafenib use, liver cancer at stage IIIC, and prior splenectomy.

A mesoporous superparamagnetic iron oxide nanoparticle as a generic drug delivery system for tumor ferroptosis therapy.

As a famous drug delivery system (DDS), mesoporous organosilica nanoparticles (MON) are degraded slowly in vivo and the degraded components are not useful for cell nutrition or cancer theranostics, and superparamagnetic iron oxide nanoparticles (SPION) are not mesoporous with low drug loading content (DLC). To overcome the problems of MON and SPION, we developed mesoporous SPIONs (MSPIONs) with an average diameter of 70 nm and pore size of 3.9 nm. Sorafenib (SFN) and/or brequinar (BQR) were loaded into the mesopores of MSPION, generating SFN@MSPION, BQR@MSPION and SFN/BQR@MSPION with high DLC of 11.5% (SFN), 10.1% (BQR) and 10.0% (SNF + BQR), demonstrating that our MSPION is a generic DDS. SFN/BQR@MSPION can be used for high performance ferroptosis therapy of tumors because: (1) the released Fe2+/3+ in tumor microenvironment (TME) can produce •OH via Fenton reaction; (2) the released SFN in TME can inhibit the cystine/glutamate reverse transporter, decrease the intracellular glutathione (GSH) and GSH peroxidase 4 levels, and thus enhance reactive oxygen species and lipid peroxide levels; (3) the released BQR in TME can further enhance the intracellular oxidative stress via dihydroorotate dehydrogenase inhibition. The ferroptosis therapeutic mechanism, efficacy and biosafety of MSPION-based DDS were verified on tumor cells and tumor-bearing mice.

Efficacy of Sorafenib-Based Therapies for Non-Small Cell Lung Cancer.

Lung cancer remains the leading cause of cancer-related deaths, with a poor prognosis. Of the two types, non-small cell lung cancer (NSCLC) is the major and most prevalent type and associated with low response rates to the current treatment options. Sorafenib, a multitargeted tyrosine kinase inhibitor used for various malignancies, gained attention for its potential efficacy in NSCLC. This review paper focuses on the findings of recent in vitro, in vivo, and clinical studies regarding the efficacy of sorafenib. Overall, sorafenib has shown definitive therapeutic potential in NSCLC cell lines, xenografts, and human subjects. Novel approaches to sorafenib delivery may improve its efficacy and should be the focus of further studies.

Inhibition of PTPRE suppresses tumor progression and improves sorafenib response in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has a poor prognosis, and the efficacy of current therapeutic strategies is extremely limited in advanced diseases. Our previous study reported that protein tyrosine phosphatase receptor epsilon (PTPRE) is a promoting factor in HCC progression. In this study, our objective was to evaluate the treatment effect of PTPRE inhibitors in different HCC preclinical models. Our results indicated that the PTPRE inhibitory compound 63 (Cpd-63) inhibited tumor cell proliferation, migration, and HCC organoid growth. Mechanism research revealed that Cpd-63 could inhibit the expression of MYC and MYC targets by inhibiting the activation of SRC. Additionally, we found that Cpd-63 could improve the response of sorafenib in HCC cells. In conclusion, we demonstrated that the PTPRE inhibitors represented a potential therapeutic agent for HCC management.

The sorafenib resistance-related gene signature predicts prognosis and indicates immune activity in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death worldwide. Most patients with advanced HCC acquire sorafenib resistance. Drug resistance reflects the heterogeneity of tumors and is the main cause of tumor recurrence and death.We identified and validated sorafenib resistance related-genes (SRGs) as prognostic biomarkers for HCC. We obtained SRGs from the Gene Expression Omnibus and selected four key SRGs using the least absolute shrinkage and selection operator, random forest, and Support Vector Machine-Recursive feature elimination machine learning algorithms. Samples from the The Cancer Genome Atlas (TCGA)-HCC were segregated into two groups by consensus clustering. Following difference analysis, 19 SRGs were obtained through univariate Cox regression analysis, and a sorafenib resistance model was constructed for risk stratification and prognosis prediction. In multivariate Cox regression analysis, the risk score was an independent predictor of overall survival (OS). Patients classified as high-risk were more sensitive to other chemotherapy drugs and showed a higher expression of the common immune checkpoints. Additionally, the expression of drug-resistance genes was verified in the International Cancer Genome Consortium cohort. A nomogram model with a risk score was established, and its prediction performance was verified by calibration chart analysis of the TCGA-HCC cohort. We conclude that there is a significant correlation between sorafenib resistance and the tumor immune microenvironment in HCC. The risk score could be used to identify a reliable prognostic biomarker to optimize the therapeutic benefits of chemotherapy and immunotherapy, which can be helpful in the clinical decision-making for HCC patients.

Combination of ethyl acetate fraction from Calotropis gigantea stem bark and sorafenib induces apoptosis in HepG2 cells.

The cytotoxicity of the ethyl acetate fraction of the Calotropis gigantea (L.) Dryand. (C. gigantea) stem bark extract (CGEtOAc) has been demonstrated in many types of cancers. This study examined the improved cancer therapeutic activity of sorafenib when combined with CGEtOAc in HepG2 cells. The cell viability and cell migration assays were applied in HepG2 cells treated with varying concentrations of CGEtOAc, sorafenib, and their combination. Flow cytometry was used to determine apoptosis, which corresponded with a decline in mitochondrial membrane potential and activation of DNA fragmentation. Reactive oxygen species (ROS) levels were assessed in combination with the expression of the phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) pathway, which was suggested for association with ROS-induced apoptosis. Combining CGEtOAc at 400 µg/mL with sorafenib at 4 µM, which were their respective half-IC50 concentrations, significantly inhibited HepG2 viability upon 24 h of exposure in comparison with the vehicle and each single treatment. Consequently, CGEtOAc when combined with sorafenib significantly diminished HepG2 migration and induced apoptosis through a mitochondrial-correlation mechanism. ROS production was speculated to be the primary mechanism of stimulating apoptosis in HepG2 cells after exposure to a combination of CGEtOAc and sorafenib, in association with PI3K/Akt/mTOR pathway suppression. Our results present valuable knowledge to support the development of anticancer regimens derived from the CGEtOAc with the chemotherapeutic agent sorafenib, both of which were administered at half-IC50, which may minimize the toxic implications of cancer treatments while improving the therapeutic effectiveness toward future medical applications.

Evaluation of the cytotoxic activity of sorafenib-loaded camel milk casein nanoparticles against hepatocarcinoma cells.

Sorafenib, a multikinase inhibitor is used to treat hepatocellular and renal carcinoma. However, a low solubility impedes its bioavailability and thus, effectiveness. This study aims to enhance its effectiveness by using novel camel milk casein nanoparticles as a delivery system. This study evaluates the cytotoxicity of sorafenib encapsulated in camel milk casein nanoparticles against human hepatocarcinoma cells (HepG2 cells) in vitro. Optimal drug loaded nanoparticles were stable for 1 month, had encapsulation efficiency of 96%, exhibited a particle size of 230 nm, zeta potential of -14.4 and poly disparity index of 0.261. Treatment with it led to cell morphology and DNA fragmentation as a characteristic of apoptosis. Flow cytometry showed G1 phase arrest of cell cycle and 26% increased apoptotic cells population upon treatment as compared to control. Sorafenib-loaded casein nanoparticles showed 6-fold increased ROS production in HepG2 cells as compared to 4-fold increase shown by the free drug. Gene and protein expression studies done by qPCR and western blotting depicted upregulation of tumor suppressor gene p53, pro-apoptotic Bax, and caspase-3 along with downregulated anti-apoptotic Bcl-2 gene and protein expression which further emphasized death by apoptosis. It is concluded regarding the feasibility of these casein nanoparticles as a delivery system with enhanced therapeutic outcomes against hepatocellular carcinoma cells.

Multi-b-value DWI to evaluate the synergistic antiproliferation and anti-heterogeneity effects of bufalin plus sorafenib in an orthotopic HCC model.

BACKGROUND: Multi-b-value diffusion-weighted imaging (DWI) with different postprocessing models allows for evaluating hepatocellular carcinoma (HCC) proliferation, spatial heterogeneity, and feasibility of treatment strategies. We assessed synergistic effects of bufalin+sorafenib in orthotopic HCC-LM3 xenograft nude mice by using intravoxel incoherent motion (IVIM), diffusion kurtosis imaging (DKI), a stretched exponential model (SEM), and a fractional-order calculus (FROC) model. METHODS: Twenty-four orthotopic HCC-LM3 xenograft mice were divided into bufalin+sorafenib, bufalin, sorafenib treatment groups, and a control group. Multi-b-value DWI was performed using a 3-T scanner after 3 weeks' treatment to obtain true diffusion coefficient Dt, pseudo-diffusion coefficient Dp, perfusion fraction f, mean diffusivity (MD), mean kurtosis (MK), distributed diffusion coefficient (DDC), heterogeneity index α, diffusion coefficient D, fractional order parameter ß, and microstructural quantity µ. Necrotic fraction (NF), standard deviation (SD) of hematoxylin-eosin staining, and microvessel density (MVD) of anti-CD31 staining were evaluated. Correlations of DWI parameters with histopathological results were analyzed, and measurements were compared among four groups. RESULTS: In the final 22 mice, f positively correlated with MVD (r = 0.679, p = 0.001). Significantly good correlations of MK (r = 0.677), α (r = -0.696), and ß (r= -0.639) with SD were observed (all p < 0.010). f, MK, MVD, and SD were much lower, while MD, α, ß, and NF were higher in bufalin plus sorafenib group than control group (all p < 0.050). CONCLUSION: Evaluated by IVIM, DKI, SEM, and FROC, bufalin+sorafenib was found to inhibit tumor proliferation and angiogenesis and reduce spatial heterogeneity in HCC-LM3 models. RELEVANCE STATEMENT: Multi-b-value DWI provides potential metrics for evaluating the efficacy of treatment in HCC. KEY POINTS: • Bufalin plus sorafenib combination may increase the effectiveness of HCC therapy. • Multi-b-value DWI depicted HCC proliferation, angiogenesis, and spatial heterogeneity. • Multi-b-value DWI may be a noninvasive method to assess HCC therapeutic efficacy.

Cost-effectiveness analysis of Tislelizumab vs Sorafenib as the first-line treatment of unresectable hepatocellular carcinoma.

BACKGROUND: To evaluate the cost-effectiveness of Tislelizumab vs Sorafenib as the first-line treatment of unresectable hepatocellular carcinoma (HCC) from the perspective of the Chinese health service system. METHODS: A lifetime partitioned survival model (PSM) was developed to cost-effectively analyze Tislelizumab vs Sorafenib as the first-line treatment of unresectable HCC. The clinical and safety data were derived from a recently randomized clinical trial (RATIONALE-301). Utilities were collected from the published literature. Costs were obtained from an open-access database (http://www.yaozh.com) and previous studies. The model cycle was 21 days, according to the RATIONALE-301 study, and the simulation period was patients' lifetime. Long-term direct medical costs and quality-adjusted life-years (QALYs) were determined. The incremental cost-effectiveness ratio (ICER) was used as the evaluation index. one-way sensitivity analysis (OSWA) and probabilistic sensitivity analysis (PSA) were used to analyze the uncertainty of parameters and to adjust and verify the stability of the baseline results. RESULTS: The Tislelizumab group generated a cost of $39,746.34 and brought health benefits to 2.146 QALYs, while the cost and utility of the Sorafenib group were $26750.95 and 1.578 QALYs, respectively. The Tislelizumab group increased QALYs by 0.568, the incremental cost was $12995.39, and the ICER was $22869.64/QALY, lower than the willingness to pay threshold (WTP). OSWA results showed that the utility of progressed disease (PD), cost of Camrelizumab, and cost of Tislelizumab were the main factors affecting the ICER. PSA results showed that, within 1000 times the Monte Carlo simulation, the cost of the Tislelizumab group was lower than three times the per capita gross domestic product (GDP) of China ($37653/QALY). The cost-effectiveness acceptability curves (CEAC) revealed that when WTP was no less than $12251.00, the Tislelizumab group was the dominant scheme, and the economic advantage grew with an increasing WTP. When WTP ≥ $19000.00, the Tislelizumab group became the absolute economic advantage. CONCLUSION: Under the current economic conditions in China, the Tislelizumab therapeutic scheme is more cost-effective than the Sorafenib therapeutic scheme for treating patients with unresectable HCC.

Low-Dose Sorafenib Promotes Cancer Stem Cell Expansion and Accelerated Tumor Progression in Soft Tissue Sarcomas.

The cancer stem cell (CSC) hypothesis postulates that heterogeneous human cancers harbor a population of stem-like cells which are resistant to cytotoxic therapies, thus providing a reservoir of relapse following conventional therapies like chemotherapy and radiation (RT). CSCs have been observed in multiple human cancers, and their presence has been correlated with worse clinical outcomes. Here, we sought to evaluate the impact of drug dosing of the multi-tyrosine kinase inhibitor, sorafenib, on CSC and non-CSCs in soft tissue sarcoma (STS) models, hypothesizing differential effects of sorafenib based on dose and target cell population. In vitro, human cancer cell lines and primary STS from surgical specimens were exposed to escalating doses of sorafenib to determine cell viability and expression of CSC marker aldehyde dehydrogenase (ALDH). In vivo, ALDHbright CSCs were isolated, exposed to sorafenib, and xenograft growth and survival analyses were performed. We observed that sarcoma CSCs appear to paradoxically respond to the tyrosine kinase inhibitor sorafenib at low doses with increased proliferation and stem-like function of CSCs, whereas anti-viability effects dominated at higher doses. Importantly, STS patients receiving neoadjuvant sorafenib and RT on a clinical trial (NCT00864032) showed increased CSCs post therapy, and higher ALDH scores post therapy were associated with worse metastasis-free survival. These data suggest that low-dose sorafenib may promote the CSC phenotype in STS with clinically significant effects, including increased tumor growth and higher rates of metastasis formation in sarcoma patients.

Long-term di-(2-ethylhexyl) phthalate exposure reduces sorafenib treatment efficacy by enhancing mesenchymal transition in hepatocellular carcinoma.

Di(2-ethylhexyl) phthalate (DEHP) is a worldwide common plasticizer. Nevertheless, DEHP is easily leached out to the environment due to the lack of covalent bonds with plastic. High dose of DEHP exposure is often observed in hemodialysis patients because of the continual usage of plastic medical devices. Although the liver is the major organ that catabolizes DEHP, the impact of long-term DEHP exposure on the sensitivity of liver cancer to chemotherapy remains unclear. In this study, we established long-term DEHP-exposed hepatocellular carcinoma (HCC) cells and two NOD/SCID mice models to investigate the effects and the underlying mechanisms of long-term DEHP exposure on chemosensitivity of HCC. The results showed long-term DEHP exposure potentially increased epithelial-mesenchymal transition (EMT) in HCC cells. Next generation sequencing showed that long-term DEHP exposure increased cell adhesion/migratory related genes expression and blunted sorafenib treatment induced genes alterations. Long-term exposure to DEHP reduced the sensitivity of HCC cells to sorafenib-induced anti-migratory effect by enhancing the EMT transcription factors (slug, twist, and ZEB1) and mesenchymal protein (vimentin) expression. In NOD/SCID mice model, we showed that long-term DEHP-exposed HCC cells exhibited higher growth rate. Regarding the anti-HCC effects of sorafenib, subcutaneous HuH7 tumor grew slowly in sorafenib-treated mice. Nonetheless, the anti-tumor growth effect of sorafenib was not observed in long-term DEHP-exposed mice. Higher mesenchymal markers and proliferating cell nuclear antigen (PCNA) expression were found in sorafenib-treated long-term DEHP-exposed mice. In conclusion, long-term DEHP exposure promoted migratory activity in HCC cells and decreased sorafenib sensitivity in tumor-bearing mice.

A novel mitochondrial unfolded protein response-related risk signature to predict prognosis, immunotherapy and sorafenib sensitivity in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common cause of cancer-associated death worldwide. The mitochondrial unfolded protein response (UPRmt) not only maintains mitochondrial integrity but also regulates cancer progression and drug resistance. However, no study has used the UPRmt to construct a prognostic signature for HCC. This work aimed to establish a novel signature for predicting patient prognosis, immune cell infiltration, immunotherapy, and chemotherapy response based on UPRmt-related genes (MRGs). Transcriptional profiles and clinical information were obtained from the TCGA and ICGC databases. Cox regression and LASSO regression analyses were applied to select prognostic genes and develop a risk model. The TIMER algorithm was used to investigate immunocytic infiltration in the high- and low-risk subgroups. Here, two distinct clusters were identified with different prognoses, immune cell infiltration statuses, drug sensitivities, and response to immunotherapy. A risk score consisting of seven MRGs (HSPD1, LONP1, SSBP1, MRPS5, YME1L1, HDAC1 and HDAC2) was developed to accurately and independently predict the prognosis of HCC patients. Additionally, the expression of core MRGs was confirmed by immunohistochemistry (IHC) staining, single-cell RNA sequencing, and spatial transcriptome analyses. Notably, the expression of prognostic MRGs was significantly correlated with sorafenib sensitivity in HCC and markedly downregulated in sorafenib-treated HepG2 and Huh7 cells. Furthermore, the knockdown of LONP1 decreased the proliferation, invasion, and migration of HepG2 cells, suggesting that upregulated LONP1 expression contributed to the malignant behaviors of HCC cells. To our knowledge, this is the first study to investigate the consensus clustering algorithm, prognostic potential, immune microenvironment infiltration and drug sensitivity based on the expression of MRGs in HCC. In summary, the UPRmt-related classification and prognostic signature could assist in determining the prognosis and personalized therapy of HCC patients from the perspectives of predictive, preventative and personalized medicine.

New Opportunities in the Systemic Treatment of Hepatocellular Carcinoma-Today and Tomorrow.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Liver cirrhosis, hepatitis B, hepatitis C, and non-alcoholic fatty liver disease represent major risk factors of HCC. Multiple different treatment options are available, depending on the Barcelona Clinic Liver Cancer (BCLC) algorithm. Systemic treatment is reserved for certain patients in stages B and C, who will not benefit from regional treatment methods. In the last fifteen years, the arsenal of available therapeutics has largely expanded, which improved treatment outcomes. Nevertheless, not all patients respond to these agents and novel combinations and drugs are needed. In this review, we aim to summarize the pathway of trials investigating the safety and efficacy of targeted therapeutics and immunotherapies since the introduction of sorafenib. Furthermore, we discuss the current evidence regarding resistance mechanisms and potential novel targets in the treatment of advanced HCC.

Vinorelbine Improves the Efficacy of Sorafenib against Hepatocellular Carcinoma: A Promising Therapeutic Approach.

Hepatocellular carcinoma (HCC) is a leading global cause of cancer-related mortality. Despite the widespread adoption of sorafenib as the standard HCC treatment, its efficacy is constrained, frequently encountering resistance. To augment the effectiveness of sorafenib, this study investigated the synergy of sorafenib and vinorelbine using 22 HCC patient-derived xenograft (PDX) models. In this study, mice bearing HCC tumors were treated with the vehicle, sorafenib (15 mg/kg), vinorelbine (3 mg/kg), and sorafenib-vinorelbine combination (Sora/Vino). Rigorous monitoring of the tumor growth and side effects coupled with comprehensive histological and molecular analyses was conducted. The overall survival (OS) of mice bearing HCC orthotopic tumors was also assessed. Our data showed a notable 86.4% response rate to Sora/Vino, surpassing rates of 31.8% for sorafenib and 9.1% for vinorelbine monotherapies. Sora/Vino significantly inhibited tumor growth, prolonged OS of mice bearing HCC orthotopic tumors (p < 0.01), attenuated tumor cell proliferation and angiogenesis, and enhanced necrosis and apoptosis. The combination therapy effectively suppressed the focal adhesion kinase (FAK) pathway, which is a pivotal player in cell proliferation, tumor angiogenesis, survival, and metastasis. The noteworthy antitumor activity in 22 HCC PDX models positions Sora/Vino as a promising candidate for early-phase clinical trials, leveraging the established use of sorafenib and vinorelbine in HCC and other cancers.

Targeting AXL induces tumor-intrinsic immunogenic response in tyrosine kinase inhibitor-resistant liver cancer.

Hepatocellular carcinoma (HCC) is an aggressive malignancy without effective therapeutic approaches. Here, we evaluate the tumor-intrinsic mechanisms that attenuate the efficacy of immune checkpoint inhibitor (ICI) that is observed in patients with advanced HCC who progress on first-line tyrosine kinase inhibitor (TKI) therapy. Upregulation of AXL observed in sorafenib- and lenvatinib-resistant HCCs is correlated with poor response towards TKI and ICI treatments. AXL upregulation protects sorafenib-resistant HCC cells from oxidative stress, mitochondrial damage, and accompanying immunogenic cell death through suppressed tumor necrosis factor-α (TNF-α) and STING-type I interferon pathways. Pharmacological inhibition of AXL abrogates the protective effect and re-sensitizes TKI-resistant HCC tumors to anti-PD-1 treatment. We suggest that targeting AXL in combination with anti-PD-1 may provide an alternative treatment scheme for HCC patients who progress on TKI treatment.