nintedanib and Liver-Neoplasms

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Traditional chemotherapy drugs are hard to reach a satisfactory therapeutic effect since advanced HCC is highly chemo-resistant. Sorafenib is an oral multikinase inhibitor that can suppress tumor cell proliferation, angiogenesis and induce cancer cell apoptosis. However, the poor solubility, rapid metabolism and low bioavailability of sorafenib greatly restricted its further clinical application. During the past decade, numerous sorafenib derivatives have been designed and synthesized to overcome its disadvantages and improve its clinical performance. This article focuses on the therapeutic effects and mechanisms of various sorafenib derivatives with modifications on the N-methylpicolinamide group, urea group, central aromatic ring or others. More importantly, this review summarizes the current status of the structure-activity relationship (SAR) of reported sorafenib derivatives, which can provide some detailed information of future directions for further structural modifications of sorafenib to discovery new anti-tumor drugs with improved clinical performance.

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Proliferation; Chemistry, Pharmaceutical; ErbB Receptors; Humans; Liver Neoplasms; Molecular Structure; Protein Kinase Inhibitors; Sorafenib

Angiogenesis is essential for tumor growth and metastasis. The main regulators of the process are the signaling cascades of VEGF-, PDGF- and FGF receptors. Inhibition of these pathways holds potential therapeutic benefit not only for cancer patients, but also for the treatment of other diseases. This paper summarizes the experimental and clinical results of studies available so far on the multi-target tyrosine kinase inhibitor nintedanib (BIBF 1120). According to these studies, nintedanib effectively inhibits VEGFR-, PDGFR- and FGFR signalization and thus the proliferation and survival of cell types which highly express these receptors (i.e. endothelial and smooth muscle cells and pericytes). In vitro studies and in vivo xenograft experiments have provided promising results. In the clinical setting, BIBF 1120 seems to be effective and well tolerated in various tumor types, such as lung, prostate, colorectal and hepatocellular carcinoma, as well as in gynecological tumors. The main adverse events are gastrointestinal toxicities and the reversible elevation of liver enzyme levels. Nintedanib might also be combined with paclitaxel, carboplatin, pemetrexed and docetaxel. There are several ongoing clinical trials testing the efficacy of BIBF 1120.

Topics: Animals; Antineoplastic Agents; Axitinib; Benzenesulfonates; Carcinoma, Hepatocellular; Clinical Trials as Topic; Colorectal Neoplasms; Digestive System; Enzyme Inhibitors; Female; Genital Neoplasms, Female; Humans; Imidazoles; Indazoles; Indoles; Liver Neoplasms; Lung Neoplasms; Male; Neoplasms; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phthalazines; Piperidines; Prostatic Neoplasms; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Quinazolines; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sorafenib; Sulfonamides; Xenograft Model Antitumor Assays

This multicentre, open-label, phase-I/randomised phase-II trial evaluated safety, pharmacokinetics, maximum-tolerated-dose (MTD) per dose-limiting toxicities (DLTs), and efficacy of nintedanib vs. sorafenib in European patients with unresectable advanced hepatocellular carcinoma (aHCC).. Phase I: Patients were stratified into two groups per baseline aminotransferase/alanine aminotransferase and Child-Pugh score; MTD was determined. Phase II: Patients were randomised 2:1 to nintedanib (MTD) or sorafenib (400-mg bid) in 28-day cycles until intolerance or disease progression. Time-to-progression (TTP, primary endpoint), overall survival (OS) and progression-free survival (PFS) were determined.. Phase-I: no DLTs observed; nintedanib MTD in both groups was 200 mg bid. Phase-II: patients (N = 93) were randomised to nintedanib (n = 62) or sorafenib (n = 31); TTP was 5.5 vs. 4.6 months (HR = 1.44 [95% CI, 0.81-2.57]), OS was 11.9 vs. 11.4 months (HR = 0.88 [95% CI, 0.52-1.47]), PFS was 5.3 vs. 3.9 months (HR = 1.35 [95% CI, 0.78-2.34]), respectively (all medians). Dose intensity and tolerability favoured nintedanib. Fewer patients on nintedanib (87.1%) vs. sorafenib (96.8%) had drug-related adverse events (AEs) or grade ≥ 3 AEs (67.7% vs. 90.3%), but more patients on nintedanib (28 [45.2%]) had AEs leading to drug discontinuation than did those on sorafenib (7 [22.6%]).. Nintedanib may have similar efficacy to sorafenib in aHCC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Disease Progression; Disease-Free Survival; Europe; Female; Humans; Indoles; Liver Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Sorafenib; Treatment Outcome

Response Evaluation Criteria in Solid Tumors (RECIST) has been shown to be a poor surrogate for survival benefit with targeted therapy in advanced hepatocellular carcinoma (HCC).. We investigated whether response evaluated using modified RECIST (mRECIST) predicted overall survival (OS) using data from two Phase II clinical trials. Analyses were conducted on pooled data from 188 patients with advanced HCC treated with nintedanib or sorafenib, of whom 180 were evaluable for response. Cox regression and Kaplan-Meier survival analyses were used to explore differences in OS between the responders and non-responders according to RECIST 1.0 and mRECIST criteria. Multivariate Cox proportional hazards models, including factors known to influence survival, were used to compare survival according to RECIST and mRECIST response.. Discordance between RECIST and mRECIST evaluation was most common for assessment of partial response (12.2%) and stable disease (13.3%). OS was significantly longer in patients with response compared to patients without response-RECIST: hazard ratio (HR) 0.325 (95% confidence interval [CI] 0.130-0.815), P=.0122; mRECIST: HR 0.544 (95% CI 0.335-0.881), P=.0122. HRs from the multivariate models used to evaluate response by RECIST or by mRECIST as predictors of OS approached significance for RECIST (0.40 [95% CI 0.16-1.01]; P=.053) and for mRECIST (0.62 [95% CI 0.38-1.01]; P=.053).. Response according to RECIST or mRECIST is associated with improved survival and should be considered as a valid endpoint for use in HCC clinical trials.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Hepatocellular; Chi-Square Distribution; Female; Humans; Indoles; Kaplan-Meier Estimate; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Multivariate Analysis; Niacinamide; Phenylurea Compounds; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Protein Kinase Inhibitors; Response Evaluation Criteria in Solid Tumors; Risk Factors; Sorafenib; Time Factors; Tomography, X-Ray Computed

Salivary gland cancers (SGCs) are uncommon and account for less than 5% of all head and neck cancers, but they are histologically heterogeneous. No specific therapy, including targeted agents, has consistently improved clinical outcomes in recurrent/metastatic SGC. Recent studies suggest that vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) play important roles in SGC. Nintedanib is a potent small-molecule, triple-receptor tyrosine kinase inhibitor (VEGFR1, VEGFR2, and VEGFR3; fibroblast growth factor receptor 1 [FGFR1], FGFR2, and FGFR3; and PDGFRα and PDGFRß). This study sought to determine the antitumor activity of nintedanib in patients with recurrent or metastatic SGC.. This open-label, multicenter, phase 2, single-arm study was conducted at 11 hospitals in South Korea. Patients with pathologically confirmed recurrent and/or metastatic SGC for whom at least 1 line of systemic chemotherapy had failed were enrolled. Nintedanib was given orally at 200 mg twice a day until disease progression or unacceptable toxicity. The primary endpoint was the response rate. The secondary endpoints were progression-free survival, overall survival, toxicity, and the disease-control rate. The Simon 2-stage minimax design was used.. The median age of the patients was 54 years, 60% were female, and 95% had an Eastern Cooperative Oncology Group performance status of 0 or 1. The majority of the patients had adenoid cystic carcinoma (65%), and 40% received at least 2 prior rounds of chemotherapy. After 20 patients were enrolled, the study was stopped because no responders were observed at stage I. There were no partial responses, but the disease-control rate was 75% (15 of 20). The median duration of stable disease was 8.2 months (range, 1.76-12.36 months). At the time of the data cutoff, with a median follow-up of 9.5 months, the median overall survival had not been reached, and the progression-free survival rate at 6 months was 60% (95% confidence interval, 0.34-0.79). Grade 3 adverse events included liver enzyme elevation (25%) and nausea/vomiting (5%). Four patients who required a dose reduction because of a grade 3 liver enzyme elevation showed no further grade 3 events.. Single-agent nintedanib did not yield a partial response but did achieve a 75% disease-control rate with long-term stabilization in SGC patients. Because of the high rate and long duration of disease control with a good safety profile, further investigation is warranted. Cancer 2017;123:1958-1964. © 2017 American Cancer Society.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Bone Neoplasms; Carcinoma, Adenoid Cystic; Carcinoma, Mucoepidermoid; Early Termination of Clinical Trials; Female; Head and Neck Neoplasms; Humans; Indoles; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Palliative Care; Pleural Neoplasms; Republic of Korea; Salivary Gland Neoplasms; Treatment Failure

This phase I, dose-escalation study evaluated the safety, preliminary efficacy and pharmacokinetics of nintedanib, a triple angiokinase inhibitor, in Japanese patients with advanced hepatocellular carcinoma and mild/moderate liver impairment. Thirty patients with unresectable hepatocellular carcinoma were enrolled to groups, depending on whether liver impairment was mild (group I, aspartate aminotransferase and alanine aminotransferase ≤2× upper limit of normal and Child-Pugh score 5 [n = 14] or 6 [n = 2]) or moderate (group II, Child-Pugh score 5-6 and aspartate aminotransferase or alanine aminotransferase >2× to ≤5× upper limit of normal [n = 7] or Child-Pugh score 7 [n = 7]); 22 patients had prior sorafenib treatment. Nintedanib was given twice daily in 28-day cycles until disease progression or unacceptable adverse events, starting at 150 mg (group I) or 100 mg (group II) and escalating to 200 mg. The primary objective was to define the maximum tolerated dose based on occurrence of dose-limiting toxicities during cycle 1 (grade ≥3 non-hematological and grade 4 hematological adverse events). No dose-limiting toxicities were reported during cycle 1 and the maximum tolerated dose for both groups was 200 mg twice daily. The most frequent adverse events were gastrointestinal (diarrhea, nausea, vomiting, and decreased appetite). No patients discontinued nintedanib due to adverse events; 31% of group I and 21% of group II had dose reductions. Median time to progression was 2.8 months (95% confidence interval, 1.05-5.52) for group I and 3.2 months (95% confidence interval, 0.95-6.70) for group II. Nintedanib showed a manageable safety profile and efficacy signals, including in patients previously treated with sorafenib. Clinical trial registration NCT01594125; 1199.120 (ClinicalTrials.gov).

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Hepatocellular; Drug Monitoring; Female; Humans; Indoles; Liver Function Tests; Liver Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Treatment Outcome

Hepatic metastases are arterially supplied, resulting in an elevated hepatic perfusion index (HPI). The purpose of this study was to use dynamic contrast-enhanced (DCE) MR imaging to quantify the HPI of metastases and the liver before and after treatment with a novel antiangiogenic drug. Ten patients with known metastatic liver disease underwent DCE-MR studies. HPIs of metastases and whole liver were derived using regions of interest (ROIs) and calculated on a pixel-by-pixel basis from quantified changes in gadopentetate dimeglumine (Gd-DTPA) concentration. The HPI measurement error prior to treatment was derived by the Bland-Altman analysis. The median HPI before and after treatment with antiangiogenic drug BIBF 1120 were compared using the Wilcoxon signed rank test. Prior to treatment, the median HPI of metastases, 0.75 +/- 0.14, was significantly higher than that of the whole liver, 0.66 +/- 0.16 (p < 0.01). Bland-Altman reproducibility coefficients of the median HPI from metastases and whole liver were 13.0 and 5.1% respectively. The median HPI of metastases decreased significantly at 28 days after treatment with BIBF 1120 (p < 0.05). This pilot study demonstrates that HPI determined using quantified Gd-DTPA concentration is reproducible and may be useful for monitoring antiangiogenic treatment response of hepatic metastases.

Topics: Adult; Aged; Angiogenesis Inhibitors; Contrast Media; Female; Gadolinium DTPA; Humans; Image Processing, Computer-Assisted; Indoles; Liver; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Neovascularization, Pathologic; Reproducibility of Results; Statistics, Nonparametric; Treatment Outcome

Nintedanib (ND) was known as a triple tyrosine kinase inhibitors, inhibiting angiogenesis and tissue fibrosis. Biguanide group has attracted much attention for its great penetrating ability to the lipid bilayer of cytomembrane and potential anti-cancer efficacy. In this study, a biguanide group (p-biguanidinobenzoic acid, CBH) decorated bovine serum albumin (CBH-AB) was synthesized as a novel functional biomaterial to prepare the ND loaded CBH-AB nanoparticles (ND-CBH-AB NPs). The results of physical and chemical properties showed that ND-CBH-AB NPs possessed high encapsulation efficiency and drug loading efficiency. In vitro cell study indicated that CBH modification on ND-CBH-AB NPs enhanced the cyctotoxicities to HepG2 cells. Furthermore, pharmacokinetic study showed that ND-CBH-AB NPs had good stability in circulation. Finally, pharmacodynamic studies were conducted, the results indicated that ND-CBH-AB NPs exhibited excellent anti-tumor effect and tumor microenvironment regulation effect. Thereby, this work provides a potential function albumin delivery system for hepatocellular carcinoma therapy.

Topics: Biguanides; Carcinoma, Hepatocellular; Humans; Indoles; Liver Neoplasms; Nanoparticles; Serum Albumin, Bovine; Tumor Microenvironment

Cirrhosis and chronic inflammation precede development of hepatocellular carcinoma (HCC) in approximately 80% of cases. We investigated immune-related gene expression patterns in liver tissues surrounding early-stage HCCs and chemopreventive agents that might alter these patterns to prevent liver tumorigenesis.. We analyzed gene expression profiles of nontumor liver tissues from 392 patients with early-stage HCC (training set, N = 167 and validation set, N = 225) and liver tissue from patients with cirrhosis without HCC (N = 216, controls) to identify changes in expression of genes that regulate the immune response that could contribute to hepatocarcinogenesis. We defined 172 genes as markers for this deregulated immune response, which we called the immune-mediated cancer field (ICF). We analyzed the expression data of liver tissues from 216 patients with cirrhosis without HCC and investigated the association between this gene expression signature and development of HCC and outcomes of patients (median follow-up, 10 years). Human liver tissues were also analyzed by histology. C57BL/6J mice were given a single injection of diethylnitrosamine (DEN) followed by weekly doses of carbon tetrachloride to induce liver fibrosis and tumorigenesis. Mice were then orally given the multiple tyrosine inhibitor nintedanib or vehicle (controls); liver tissues were collected and histology, transcriptome, and protein analyses were performed. We also analyzed transcriptomes of liver tissues collected from mice on a choline-deficient high-fat diet, which developed chronic liver inflammation and tumors, orally given aspirin and clopidogrel or the anti-inflammatory agent sulindac vs mice on a chow (control) diet.. We found the ICF gene expression pattern in 50% of liver tissues from patients with cirrhosis without HCC and in 60% of nontumor liver tissues from patients with early-stage HCC. The liver tissues with the ICF gene expression pattern had 3 different features: increased numbers of effector T cells; increased expression of genes that suppress the immune response and activation of transforming growth factor β signaling; or expression of genes that promote inflammation and activation of interferon gamma signaling. Patients with cirrhosis and liver tissues with the immunosuppressive profile (10% of cases) had a higher risk of HCC (hazard ratio, 2.41; 95% confidence interval, 1.21-4.80). Mice with chemically induced fibrosis or diet-induced steatohepatitis given nintedanib or aspirin and clopidogrel down-regulated the ICF gene expression pattern in liver and developed fewer and smaller tumors than mice given vehicle.. We identified an immune-related gene expression pattern in liver tissues of patients with early-stage HCC, called the ICF, that is associated with risk of HCC development in patients with cirrhosis. Administration of nintedanib or aspirin and clopidogrel to mice with chronic liver inflammation caused loss of this gene expression pattern and development of fewer and smaller liver tumors. Agents that alter immune regulatory gene expression patterns associated with carcinogenesis might be tested as chemopreventive agents in patients with cirrhosis.

Topics: Animals; Anticarcinogenic Agents; Aspirin; Biomarkers, Tumor; Carcinoma, Hepatocellular; Case-Control Studies; Cell Transformation, Neoplastic; Clopidogrel; Diethylnitrosamine; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Indoles; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Mice, Inbred C57BL; Transcriptome; Tumor Escape; Tumor Microenvironment

Nintedanib, a triple angiokinase inhibitor, is currently being evaluated against advanced HCC in phase I/II clinical trials. Here, we report the underlying molecular mechanism by which nintedanib (BIBF-1120) induces an anti-HCC effect.. To further elucidate whether the effect of nintedanib on SHP-1 is dependent on its angiokinase inhibition activity, we developed a novel kinase-independent derivative of nintedanib, ΔN. HCC cell lines were treated with nintedanib or its derivative (ΔN) and apoptosis, signal transduction, and phosphatase activity were analyzed. Purified SHP-1 proteins or HCC cells expressing deletion N-SH2 domain or D61A point mutants were used to investigate the potential effect of nintedanib on SHP-1. In vivo efficacy was determined in nude mice with HCC subcutaneous xenografts (n⩾8 mice).. Nintedanib induced anti-proliferation in HCC cell lines by targeting STAT3. Ectopic STAT3 abolished nintedanib-mediated apoptosis in HCC cells. Nintedanib further activated SHP-1 in purified SHP-1 proteins suggesting that nintedanib directly affects SHP-1 for STAT3 inhibition. HCC cells or recombinant SHP-1 proteins expressing deletion of N-SH2 domain or D61A mutants restored the activity of nintedanib suggesting that the auto-inhibition structure of SHP-1 was relieved by nintedanib. Although ΔN only retained the backbone of nintedanib without kinase activity, ΔN still induced substantial anti-HCC activity in vitro and in vivo by targeting STAT3.. Nintedanib induced significant anti-HCC activity independent of angiokinase inhibition activity in a preclinical HCC model by relieving autoinhibition of SHP-1. Our findings provide new mechanistic insight into the inhibition of HCC growth by nintedanib.

Topics: Animals; Antineoplastic Agents; Apoptosis; Binding Sites; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Humans; Indoles; Liver Neoplasms; Male; Mice; Mice, Nude; Models, Molecular; Mutant Proteins; Protein Conformation; Protein Kinase Inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Receptor Protein-Tyrosine Kinases; Signal Transduction; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

BIBF 1120 is a potent, orally available triple angiokinase inhibitor that inhibits VEGF receptors (VEGFR) 1, 2, and 3, fibroblast growth factor receptors, and platelet-derived growth factor receptors. This study examined the antitumor effects of BIBF 1120 on hepatocellular carcinoma (HCC) and attempted to identify a pharmacodynamic biomarker for use in early clinical trials.. We evaluated the antitumor and antiangiogenic effects of BIBF 1120 against HCC cell line both in vitro and in vivo. For the pharmacodynamic study, the phosphorylation levels of VEGFR2 in VEGF-stimulated peripheral blood leukocytes (PBL) were evaluated in mice inoculated with HCC cells and treated with BIBF 1120.. BIBF 1120 (0.01 μmol/L) clearly inhibited the VEGFR2 signaling in vitro. The direct growth inhibitory effects of BIBF 1120 on four HCC cell lines were relatively mild in vitro (IC(50) values: 2-5 μmol/L); however, the oral administration of BIBF 1120 (50 or 100 mg/kg/d) significantly inhibited the tumor growth and angiogenesis in a HepG2 xenograft model. A flow cytometric analysis revealed that BIBF 1120 significantly decreased the phosphotyrosine (pTyr) levels of VEGFR2(+)CD45(dim) PBLs and the percentage of VEGFR2(+)pTyr(+) PBLs in vivo; the latter parameter seemed to be a more feasible pharmacodynamic biomarker.. We found that BIBF 1120 exhibited potent antitumor and antiangiogenic activity against HCC and identified VEGFR2(+)pTyr(+) PBLs as a feasible and noninvasive pharmacodynamic biomarker in vivo.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Biomarkers; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Female; Flow Cytometry; Humans; Indoles; Inhibitory Concentration 50; Leukocytes; Liver Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Vascular Endothelial Growth Factor Receptor-2