Multikinase Inhibitor Sorafenib Research Articles

Lenvatinib rechallenge after failure of lenvatinib and sorafenib in metastatic thyroid cancer.

The oral multikinase inhibitors sorafenib and lenvatinib are currently available as first-line treatment for patients with unresectable or metastatic thyroid cancer. However, treatment options for patients who are refractory to these multikinase inhibitors are limited. This study aimed to evaluate the safety and efficacy of rechallenged lenvatinib after failure of both lenvatinib and sorafenib in patients with metastatic thyroid cancer in the real-world clinical practice. We retrospectively reviewed the data of consecutive 16 patients with metastatic thyroid cancer who received lenvatinib as a rechallenge after failure of initial lenvatinib and sorafenib treatment at Shizuoka Cancer Center between 2016 and 2023. Of these, the initial lenvatinib was discontinued in 12 patients owing to progressive disease, in 3 patients owing to adverse events, and in 1 patient owing to both. The overall response rate was 6.7%, and disease control was achieved by rechallenge with lenvatinib in all patients with the target lesions. The median progression free survival after rechallenging with lenvatinib was 15.0 months. No new signs of toxicity were observed after rechallenging with lenvatinib. Our findings suggest that rechallenge with lenvatinib after failure of both lenvatinib and sorafenib showed manageable safety and modest efficacy in patients with metastatic thyroid cancer in clinical practice. The strategy of lenvatinib rechallenge may provide an alternative option for patients with no targetable driver genes or when selective kinase inhibitors are not indicated.

Antiproliferative Activity of N-Acylhydrazone Derivative on Hepatocellular Carcinoma Cells Involves Transcriptional Regulation of Genes Required for G2/M Transition.

Liver cancer is the second leading cause of cancer-related death in males. It is estimated that approximately one million deaths will occur by 2030 due to hepatic cancer. Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer subtype and is commonly diagnosed at an advanced stage. The drug arsenal used in systemic therapy for HCC is very limited. Multikinase inhibitors sorafenib (Nexavar®) and lenvatinib (Lenvima®) have been used as first-line drugs with modest therapeutic effects. In this scenario, it is imperative to search for new therapeutic strategies for HCC. Herein, the antiproliferative activity of N-acylhydrazone derivatives was evaluated on HCC cells (HepG2 and Hep3B), which were chemically planned on the ALL-993 scaffold, a potent inhibitor of vascular endothelial growth factor 2 (VEGFR2). The substances efficiently reduced the viability of HCC cells, and the LASSBio-2052 derivative was the most effective. Further, we demonstrated that LASSBio-2052 treatment induced FOXM1 downregulation, which compromises the transcriptional activation of genes required for G2/M transition, such as AURKA and AURKB, PLK1, and CDK1. In addition, LASSBio-2052 significantly reduced CCNB1 and CCND1 expression in HCC cells. Our findings indicate that LASSBio-2052 is a promising prototype for further in vivo studies.

Identification of differentially expressed mRNA/lncRNA modules in acutely regorafenib-treated sorafenib-resistant Huh7 hepatocellular carcinoma cells.

The multikinase inhibitor sorafenib is the standard first-line treatment for advanced hepatocellular carcinoma (HCC), but many patients become sorafenib-resistant (SR). This study investigated the efficacy of another kinase inhibitor, regorafenib (Rego), as a second-line treatment. We produced SR HCC cells, wherein the PI3K-Akt, TNF, cAMP, and TGF-beta signaling pathways were affected. Acute Rego treatment of these cells reversed the expression of genes involved in TGF-beta signaling but further increased the expression of genes involved in PI3K-Akt signaling. Additionally, Rego reversed the expression of genes involved in nucleosome assembly and epigenetic gene expression. Weighted gene co-expression network analysis (WGCNA) revealed four differentially expressed long non-coding RNA (DElncRNA) modules that were associated with the effectiveness of Rego on SR cells. Eleven putative DElncRNAs with distinct expression patterns were identified. We associated each module with DEmRNAs of the same pattern, thus obtaining DElncRNA/DEmRNA co-expression modules. We discuss the potential significance of each module. These findings provide insights and resources for further investigation into the potential mechanisms underlying the response of SR HCC cells to Rego.

An effective two-stage NMBzA-induced rat esophageal tumor model revealing that the FAT-Hippo-YAP1 axis drives the progression of ESCC

Rat model of N-nitrosomethylbenzylamine (NMBzA)-induced esophageal squamous cell carcinoma (ESCC) is routinely used to study ESCC initiation, progression and new therapeutic strategies. However, the model is time-consuming and malignant tumor incidences are low. Here, we report the usage of multi-kinase inhibitor sorafenib as a tumor promoter to establish an efficient two-stage NMBzA-induced rat ESCC carcinogenesis model, resulting in increments of tumor incidences and shortened tumor formation times. By establishing the model and applying whole-genome sequencing, we discover that benign papillomas and malignant ESCCs harbor most of the “driver” events found in rat ESCCs (e.g. recurrent mutations in Ras family, the Hippo and Notch pathways and histone modifier genes) and the mutational landscapes of rat and human ESCCs overlap extensively. We generate tumor cell lines derived from NMBzA-induced papillomas and ESCCs, showing that papilloma cells retain more characteristics of normal epithelial cells than carcinoma cells, especially their exhibitions of normal rat cell karyotypes and inabilities of forming tumors in immunodeficient mice. Three-dimensional (3-D) organoid cultures and single cell RNA sequencing (scRNA-seq) indicate that, when compared to control- and papilloma-organoids, ESCC-organoids display salient abnormalities at tissue and single-cell levels. Multi-omic analyses indicate that NMBzA-induced rat ESCCs are accompanied by progressive hyperactivations of the FAT-Hippo-YAP1 axis and siRNA or inhibitors of YAP1 block the growth of rat ESCCs. Taken together, these studies provide a framework of using an effective rat ESCC model to investigate multilevel functional genomics of ESCC carcinogenesis, which justify targeting YAP1 as a therapeutic strategy for ESCC.

Electrolyte disorders induced by six multikinase inhibitors therapy for renal cell carcinoma: a large-scale pharmacovigilance analysis

To provide evidence for optimization of multi-kinase inhibitors (MKIs) use in the clinic, we use the public database to describe and evaluate electrolyte disorders (EDs) related to various MKIs treated for renal cell carcinoma. We analyzed spontaneous reports submitted to the Food and Drug Administration Adverse Events Reporting System (FAERS) in an observational and retrospective manner. Selecting electrolyte disorders' adverse events to multikinase inhibitors (axitinib, cabozantinib, lenvatinib, pazopanib, sunitinib, and sorafenib). We used Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) algorithms to analyze suspected adverse reactions of electrolyte disorders induced by MKIs (which were treated for renal cell carcinoma) between January 2004 and December 2022. As of December 2022, 2772 MKIs (which were treated for renal cell carcinoma) ICSRs were related to electrolyte disorders AEs. In general, there were more AEs cases in males, except lenvatinib and 71.8% of the cases were submitted from North America. ICSRs in this study, the age group most frequently affected by electrolyte disorders AEs was individuals aged 45–64 years for axitinib, cabozantinib, pazopanib, and sunitinib, whereas electrolyte disorders AEs were more common in older patients (65–74 years) for sorafenib and lenvatinib. For all EDs documented in ICSRs (excluding missing data), the most common adverse outcome was hospitalization(1429/2674, 53.4%), and the most serious outcome was death/life-threat(281/2674, 10.5%). The prevalence of mortality was highest for sunitinib-related EDs (145/616, 23.5%), excluding missing data (n = 68), followed by cabozantinib-related EDs (20/237, 8.4%), excluding missing data (n = 1). The distribution of time-to-onset of Each drug-related ICSRs was not all the same, and the difference was statistically significant (P = 0.001). With the criteria of ROR, the six MKIs were all significantly associated with electrolyte disorders AEs, the strongest association was the association between cabozantinib and hypermagnesaemia. MKIs have been reported to have significant electrolyte disorders AEs. Patients and physicians need to recognize and monitor these potentially fatal adverse events.

Identification of Keratinocyte Cytoprotectants against Toxicity by the Multikinase Inhibitor Sorafenib Using Drug Repositioning

Hand-foot skin reaction (HFSR) is the most common adverse event of multikinase inhibitors (MKI), such as sorafenib. Although HFSR is not life-threatening, severe cases impair quality of life because of pain and reduced activities of daily living. However, the pathological mechanisms of HFSR have not yet been elucidated in detail, and there is currently no effective treatment. We aimed to identify keratinocyte cytoprotectants against sorafenib toxicity.The screening of cytoprotectants against sorafenib toxicity was performed using cultured normal human epidermal keratinocytes (NHEKs) or a reconstructed human epidermis (RHE) model and off-patent approved drugs in the Prestwick Chemical library. Among 1273 drugs in the chemical library, 8 dose-dependently increased cell viability by more than 200% in the presence of sorafenib. In the presence of sorafenib, the number of proliferating cell nuclear antigen- positive cell was significantly higher in clofazimine-, cyclosporin A-, and itraconazole-treated RHE models than in sorafenib-treated models. And, candidate drugs suppressed sorafenib-induced apoptosis in NHEKs. In addition, clofazimine, itraconazole and pyrvinium pamoate significantly recovered the phosphorylation of ERK1/2 in the presence of sorafenib. Collectively, hit drugs promoted cell viability and normalized keratinocyte proliferation in the presence of sorafenib. These candidate drugs have potential as treatments for MKI-induced HFSR.

Utilizing CD44v6 and V600EBRAF-mutation for in vitro targeted combination therapy of thyroid carcinomas

AimThe aim of this study was to assess the feasibility of targeted therapy of thyroid carcinoma, first exploring potential targets BRAF, EGFR and CD44v6 in patient material through immunohistochemistry and mutation analysis. Materials and methodsA patient cohort (n = 22) consisting of seven papillary (PTC), eight anaplastic (ATC) and seven follicular (FTC) thyroid carcinomas were evaluated. Additionally, eight thyroid carcinoma cells lines were analyzed for CD44v6-expression and sensitivity to the multi-kinase inhibitor sorafenib (Nexavar®), which targets numerous serine/threonine and tyrosine kinases, including the Raf family kinases. Targeted therapy using 131I-AbN44v6, a novel anti-CD44v6 antibody, and/or sorafenib was evaluated in 3D multicellular tumor spheroids. ResultsOf the two cell surface proteins, EGFR and CD44v6, the latter was overexpressed in >80 % of samples, while EGFR-expression levels were moderate at best in only a few samples. BRAF mutations were more common in PTC patient samples than in ATC samples, while FTC samples did not harbor BRAF mutations. CD44v6-expression levels in the thyroid carcinoma cell lines were more heterogenous compared to patient samples, while BRAF mutational status was in line with the original tumor type. Monotherapy in 3D multicellular ATC tumor spheroids with either 131I-AbN44v6 or sorafenib resulted in delayed spheroid growth. The combination of 131I-AbN44v6 and sorafenib was the most potent and resulted in significantly impaired spheroid growth. ConclusionThis “proof of concept” targeted therapy study in the in vitro ATC 3D multicellular tumor spheroids indicated applicability of utilizing CD44v6 for molecular radiotherapy both as a monotherapy and in combination with sorafenib.

The New Era of Systemic Treatment for Hepatocellular Carcinoma: From the First Line to the Optimal Sequence.

Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and is considered a major global health problem as one of the leading causes of cancer-related death in the world. Due to the increase in life expectancy and the epidemiological growth of specific risk factors, such as metabolic dysfunction-associated steatotic liver disease (MASLD), the incidence of HCC is growing globally, and mortality rates are still high. Moreover, patients frequently present at an intermediate or advanced tumor stage, when curative treatments, such as surgical resection, liver transplantation or ablation are no longer applicable. In these cases, trans-arterial chemoembolization (TACE), trans-arterial radioembolization (TARE), and systemic therapy are the only suitable options to achieve disease control. The multi-kinase inhibitor Sorafenib has been the only systemic treatment available for unresectable advanced HCC for almost a decade, but in the last couple of years new therapeutic options have emerged. Recent advances in understanding the interactions between the tumor and its microenvironment, especially cancer immune escape, led to the advent of immunotherapy. Currently, first-line systemic treatment for HCC is represented by the combination of the immune checkpoint inhibitor (ICI) Atezolizumab plus Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, but many other ICIs have been investigated, such as Nivolumab, Pembrolizumab, Durvalumab and Ipilimumab. However, the problem of second- and third-line therapies, and the correct sequence of treatments remains open and is not addressed in most studies. This explains the urge to find new systemic treatments that can improve the survival and quality of life in patients that can go beyond the first line of treatment. The aim of this paper is to offer a complete overview of the most recent innovations in systemic treatments for unresectable locally advanced and metastatic HCC, including emerging therapies, with a particular focus on treatment sequences. Moreover, we will provide an outlook on possible future approaches to patients who progress beyond first-line therapies.

Phase 1/2 Study of Sorafenib Added to Cladribine, High-Dose Cytarabine, G-CSF, and Mitoxantrone in Untreated AML.

The multikinase inhibitor sorafenib improves event-free survival (EFS) when used with 7+3 in younger adults with newly diagnosed acute myeloid leukemia (AML) irrespective of FLT3 mutation status. Here, we evaluated adding sorafenib to CLAG-M (cladribine, high-dose cytarabine, G-CSF, mitoxantrone) in a phase 1/2 trial of 81 adults age ≤60 years with newly diagnosed AML or high-grade myeloid neoplasm. Forty-six patients were treated in phase 1 with escalating doses of sorafenib and mitoxantrone. No maximum tolerated dose was reached, and a regimen including mitoxantrone at 18 mg/m2/day and sorafenib 400 mg twice daily was declared the recommended phase 2 dose (RP2D). Among 41 patients treated at the RP2D, a measurable residual disease-negative complete remission (MRDneg CR) rate of 83% (95% confidence interval [CI]: 68-93%) was obtained. Four-week mortality was 2% (95% CI: 0-13%). One-year overall survival (OS) and EFS were 80% (95% CI: 69-94%) and 76% (95% CI 64-90%), without significant difference in MRDneg CR rates, OS, or EFS between patients with or without FLT3-mutated disease. Comparing outcomes with CLAG-M/sorafenib to a matched cohort of 76 patients treated with CLAG-M alone, multivariable adjusted survival estimates were improved for the 41 patients receiving CLAG-M/sorafenib at RP2D (OS: hazard ratio [HR]=0.24 [95% CI: 0.07-0.82], P=0.023; EFS: HR=0.16 [95% CI: 0.05-0.53], P=0.003). Statistically significant benefit was limited to patients with intermediate-risk disease (in univariate analysis, P=0.01 for OS and P=0.02 for EFS). These data suggest CLAG-M/sorafenib is safe and improves OS and EFS relative to CLAG-M alone, with benefit primarily for patients with intermediate-risk disease. The trial is registered on clinicialtrials.gov as NCT02728050.

The role of lenvatinib in the era of immunotherapy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) frequently presents as advanced stage with poor prognosis and high mortality. Systemic treatment is the treatment of choice for advanced disease. In 2007, the first multi-kinase inhibitor (MKI) sorafenib was approved and shown to modestly prolong overall survival (OS). The progress of systemic therapy has been slow afterwards until 2018 when lenvatinib, another MKI, was shown to be non-inferior to sorafenib on median OS as the first-line therapy for HCC. Since then, remarkable progress has been achieved on the treatment of advanced HCC, including the development of second-line targeted treatment, including regorafenib, cabozantinib and ramucirumab from 2017 to 2019. A growing focus has been placed on immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1), its ligand PD-L1, and cytotoxic T-lymphocyte-associated protein 4. These ICIs have proven their potency in treating HCC as both initial and subsequent line of therapy. At present, both regimens of atezolizumab combined with bevacizumab, as well as the combination of tremelimumab and durvalumab, are recommended as the first-line treatments based on positive phase III clinical trials. With the advancement of ICIs, it is anticipated that the role of MKIs in the treatment of HCC will evolve. In this article, lenvatinib, one of the most commonly used MKIs in HCC, is chosen to be reviewed.

Psychiatric adverse reactions to non-selective RET multi-kinase inhibitors: a large-scale pharmacovigilance analysis.

Objective: The development of non-selective multi-kinase inhibitors (MKIs) has improved the. survival outcomes of patients with cancers. Psychiatric disorders represent an MKIs related AE of particular concern, as they are often ignored and may harm the patient's personal and social functioning. Therefore, we use the public database to describe and evaluate psychiatric adverse events related to various non-selective RET MKIs. Provide evidence for optimizing drug administration in the clinic. Methods: We analyzed spontaneous reports submitted to the Food and Drug Administration Adverse Events Reporting System FDA Adverse Event Reporting System in an observational and retrospective manner. Selecting psychiatric AEs to non-selective RET multikinase inhibitors (sorafenib, lenvatinib, vandetanib, cabozantinib, and sunitinib). We used Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) algorithms to analyze suspected adverse reactions of psychiatric related induced by non-selective RET MKIs between January 2004 and September 2022. Results: As of September 2022, 1,108 non-selective RET MKIs ICSRs were related to psychiatric AEs. 706 were ADR ICSRs, and 402 were non-ADR ICSRs. There were more ADR cases in males (69.5%), and 71.8% of the cases were submitted from North America. The age group most frequently affected by psychiatric ADRs was individuals aged 50-64years for sorafenib, whereas 65-74years for sunitinib, cabozantinib, and lenvatinib. In all psychiatric ADRs ICSRs, excluding missing data (n = 329), the most common adverse outcome was hospitalization (260/377, 69.0%), and the most serious was death (100/377, 26.5%). What calls for special attention is that the percentage of death rate for sunitinib was highest (24/54, 44.4%) in sunitinib-related psychiatric ADRs ICSRs, (excluding missing data, n = 44), followed by lenvatinib (4/14, 28.6%). Based on ROR, PRR, BCPNN, and MGPS methods, sorafenib, sunitinib, cabozantinib, and lenvatinib are significantly associated with all ADRs, the strongest association was the association between cabozantinib and feeding disorder. Conclusion: Despite the limitations, our study found that, except for vandetanib, other four drugs have been reported to have significant psychiatric side effects. Clinicians need to recognize and monitor these potentially fatal adverse events. If it is suitable for treatment with vandetanib, doctors should choose vandetanib for treatment.

Targeting the YAP/TAZ mechanotransducers in solid tumour therapeutics.

Targeting the YAP/TAZ mechanotransducers in solid tumour therapeutics.

Vascular response patterns to targeted therapies in murine breast cancer models with divergent degrees of malignancy

BackgroundResponse assessment of targeted cancer therapies is becoming increasingly challenging, as it is not adequately assessable with conventional morphological and volumetric analyses of tumor lesions. The tumor microenvironment is particularly constituted by tumor vasculature which is altered by various targeted therapies. The aim of this study was to noninvasively assess changes in tumor perfusion and vessel permeability after targeted therapy in murine models of breast cancer with divergent degrees of malignancy.MethodsLow malignant 67NR or highly malignant 4T1 tumor-bearing mice were treated with either the multi-kinase inhibitor sorafenib or immune checkpoint inhibitors (ICI, combination of anti-PD1 and anti-CTLA4). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with i.v. injection of albumin-binding gadofosveset was conducted on a 9.4 T small animal MRI. Ex vivo validation of MRI results was achieved by transmission electron microscopy, immunohistochemistry and laser ablation-inductively coupled plasma-mass spectrometry.ResultsTherapy-induced changes in tumor vasculature differed between low and highly malignant tumors. Sorafenib treatment led to decreased tumor perfusion and endothelial permeability in low malignant 67NR tumors. In contrast, highly malignant 4T1 tumors demonstrated characteristics of a transient window of vascular normalization with an increase in tumor perfusion and permeability early after therapy initiation, followed by decreased perfusion and permeability parameters. In the low malignant 67NR model, ICI treatment also mediated vessel-stabilizing effects with decreased tumor perfusion and permeability, while ICI-treated 4T1 tumors exhibited increasing tumor perfusion with excessive vascular leakage.ConclusionDCE-MRI enables noninvasive assessment of early changes in tumor vasculature after targeted therapies, revealing different response patterns between tumors with divergent degrees of malignancy. DCE-derived tumor perfusion and permeability parameters may serve as vascular biomarkers that allow for repetitive examination of response to antiangiogenic treatment or immunotherapy.

Current and novel approaches in the pharmacological treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumours worldwide. The mortality-to-incidence ratio is up to 91.6% in many countries, representing the third leading cause of cancer-related deaths. Systemic drugs, including the multikinase inhibitors sorafenib and lenvatinib, are first-line drugs used in HCC treatment. Unfortunately, these therapies are ineffective in most cases due to late diagnosis and the development of tumour resistance. Thus, novel pharmacological alternatives are urgently needed. For instance, immune checkpoint inhibitors have provided new approaches targeting cells of the immune system. Furthermore, monoclonal antibodies against programmed cell death-1 have shown benefits in HCC patients. In addition, drug combinations, including first-line treatment and immunotherapy, as well as drug repurposing, are promising novel therapeutic alternatives. Here, we review the current and novel pharmacological approaches to fight HCC. Preclinical studies, as well as approved and ongoing clinical trials for liver cancer treatment, are discussed. The pharmacological opportunities analysed here should lead to significant improvement in HCC therapy.

1066 Development of keratinocyte cytoprotectant against toxicity of multikinase inhibitor sorafenib

1066 Development of keratinocyte cytoprotectant against toxicity of multikinase inhibitor sorafenib

Effects of Voluntary Wheel Running Exercise on Chemotherapy-Impaired Cognitive and Motor Performance in Mice.

Chemotherapy-induced cognitive impairment (chemobrain) and muscle wasting (cachexia) are persisting side effects which adversely affect the quality of life of cancer survivors. We therefore investigated the efficacy of physical exercise as a non-pharmacological intervention to reverse the adverse effects of chemotherapy. We examined whether physical exercise in terms of voluntary wheel running could prevent chemotherapy-induced cognitive and motor impairments in mice treated with the multi-kinase inhibitor sorafenib. Adult male BALB/c mice were subdivided into runner and non-runner groups and orally administered with sorafenib (60 mg/kg) or vehicle continuously for four weeks. Mice could freely access the running wheel anytime during sorafenib or vehicle treatment. We found that sorafenib treatment reduced body weight gain (% of change, vehicle: 3.28 ± 3.29, sorafenib: -9.24 ± 1.52, p = 0.0004), impaired hippocampal-dependent spatial memory in the Y maze (exploration index, vehicle: 35.57 ± 11.38%, sorafenib: -29.62 ± 7.90%, p < 0.0001), increased anhedonia-like behaviour in the sucrose preference test (sucrose preference, vehicle: 66.57 ± 3.52%, sorafenib: 44.54 ± 4.25%, p = 0.0005) and impaired motor skill acquisition in rotarod test (latency to fall on day 1: 37.87 ± 8.05 and day 2: 37.22 ± 12.26 s, p > 0.05) but did not induce muscle wasting or reduce grip strength. Concomitant voluntary running reduced anhedonia-like behaviour (sucrose preference, sedentary: 44.54 ± 4.25%, runners: 59.33 ± 4.02%, p = 0.0357), restored impairment in motor skill acquisition (latency to fall on day 1: 50.85 ± 15.45 and day 2: 168.50 ± 37.08 s, p = 0.0004), but failed to rescue spatial memory deficit. Immunostaining results revealed that sorafenib treatment did not affect the number of proliferating cells and immature neurons in the hippocampal dentate gyrus (DG), whereas running significantly increased cell proliferation in both vehicle- (total Ki-67+ cells, sedentary: 16,687.34 ± 72.63, exercise: 3320.03 ± 182.57, p < 0.0001) and sorafenib-treated mice (Ki-67+ cells in the ventral DG, sedentary: 688.82.34 ± 38.16, exercise: 979.53 ± 73.88, p < 0.0400). Our results suggest that spatial memory impairment and anhedonia-like behaviour precede the presence of muscle wasting, and these behavioural deficits are independent of the changes in adult hippocampal neurogenesis. Running effectively prevents body weight loss, improves motor skill acquisition and reduces anhedonia-like behaviour associated with increased proliferating cells and immature neurons in DG. Taken together, they support physical exercise rehabilitation as an effective strategy to prevent chemotherapy side effects in terms of mood dysregulation and motor deficit.

Sorafenib increases cytochrome P450 lipid metabolites in patient with hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death, and medical treatment options are limited. The multikinase inhibitor sorafenib was the first approved drug widely used for systemic therapy in advanced HCC. Sorafenib might affect polyunsaturated fatty acids (PUFA)-derived epoxygenated metabolite levels, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of cytochrome-P450 (CYP)-derived epoxide metabolites derived from PUFA, such as omega-6 arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding dihydroxy metabolites. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) have shown that they can promote tumor growth and metastasis, while DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this study, we found a significant increase in EET levels in 43 HCC patients treated with sorafenib and a trend towards increased levels of DHA-derived 19,20-EDP. We demonstrate that the effect of sorafenib on CYP- metabolites led to an increase of 19,20-EDP and its dihydroxy metabolite, whereas DHA plasma levels decreased under sorafenib treatment. These data indicate that specific supplementation with DHA could be used to increase levels of the epoxy compound 19,20-EDP with potential anti-tumor activity in HCC patients receiving sorafenib therapy.

Synthesis and Anticancer Evaluation of New Indole-Based Tyrphostin Derivatives and Their (p-Cymene)dichloridoruthenium(II) Complexes.

New N-alkylindole-substituted 2-(pyrid-3-yl)-acrylonitriles with putative kinase inhibitory activity and their (p-cymene)Ru(II) piano-stool complexes were prepared and tested for their antiproliferative efficacy in various cancer models. Some of the indole-based derivatives inhibited tumor cell proliferation at (sub-)micromolar concentrations with IC50 values below those of the clinically relevant multikinase inhibitors gefitinib and sorafenib, which served as positive controls. A focus was set on the investigation of drug mechanisms in HCT-116 p53-knockout colon cancer cells in order to evaluate the dependence of the test compounds on p53. Colony formation assays as well as experiments with tumor spheroids confirmed the excellent antineoplastic efficacy of the new derivatives. Their mode of action included an induction of apoptotic caspase-3/7 activity and ROS formation, as well as anti-angiogenic properties. Docking calculations with EGFR and VEGFR-2 identified the two 3-aryl-2-(pyrid-3-yl)acrylonitrile derivatives 2a and 2b as potential kinase inhibitors with a preferential activity against the VEGFR-2 tyrosine kinase. Forthcoming studies will further unveil the underlying mode of action of the promising new derivatives as well as their suitability as an urgently needed novel approach in cancer treatment.

Multikinase Inhibitor Treatment Patterns for Advanced Thyroid Cancer in Japan: An Administrative Claims Database Study.

The multikinase inhibitors (MKIs) sorafenib, lenvatinib, and vandetanib are approved for advanced thyroid cancer (TC) in Japan. How sequential treatment with MKIs is conducted in Japanese clinical practice is unknown. This retrospective observational cohort study used a Japanese administrative claims database (April 2008-September 2021). Patients with a confirmed TC subtype diagnosis of papillary (PTC), follicular (FTC), medullary (MTC), or anaplastic (ATC), who received MKI treatment after TC diagnosis within the index period (June 2014-August 2021), were included. Overall MKI treatment duration was estimated by Kaplan-Meier analysis. The analysis population included 795 patients (PTC, N = 447; FTC, N = 86; MTC, N = 32; ATC, N = 230). Median age was ≥ 64years; most patients (> 60%) were female except for the MTC subgroup (43.8%). First-line (1L) MKI treatment was mainly lenvatinib for PTC (81.7%), FTC (83.7%), and ATC (97.8%), and vandetanib for MTC (62.5%). Among patients discontinuing 1L MKI treatment and evaluable for subsequent therapy [PTC: 57.9% (259/447); FTC: 48.8% (42/86); MTC: 62.5% (20/32); ATC: 70.4% (162/230)], 26.3% (68/259), 21.4% (9/42), 50.0% (10/20), and 4.9% (8/162) of PTC, FTC, MTC, and ATC patients, respectively, received second-line (2L) treatment. Median (95% CI) overall MKI treatment duration was 21.2 (17.9-27.5), 43.9 (30.9-not assessable), 39.0 (17.7-not assessable), and 4.0 (3.0-4.8) months for PTC, FTC, MTC, and ATC, respectively. Advanced TC treatment options are limited. In this study, most patients received only 1L MKI treatment; of those who discontinued 1L, ≤ 50% progressed to 2L.

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.