HCC therapies—lessons learned

Wörns, Marcus‐Alexander; Galle, Peter R.

doi:10.1038/nrgastro.2014.10

Cited by 130 publications

(125 citation statements)

References 37 publications

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“…Preclinical, clinical, and comparison studies in humans using a DNA plasmid containing H19 regulatory sequences that drive the expression of an intracellular toxin (diphtheria toxin A-fragment) have demonstrated promising results in several types of carcinoma. 27 Further, our preclinical study in a murine model also indicated that stable overexpression of H19 promotes tumor formation of glioblastoma cells and induces tumor cell proliferation and angiogenesis in vivo. Therefore, we believe that H19 plays an important role in tumorigenicity and stemness of glioblastoma cells and thus may represent a therapeutic target for treatment of glioblastoma in the future.…”

Section: Discussionmentioning

confidence: 88%

Increased level of H19 long noncoding RNA promotes invasion, angiogenesis, and stemness of glioblastoma cells

Jiang

Yan

et al. 2016

JNS

155

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M alignant gliomas are the most common type of primary malignant brain tumor, and more than half of all gliomas are glioblastomas (Grade IV astrocytoma), one of the most aggressive and lethal types of brain tumor. Glioblastoma cells easily infiltrate into the normal cerebral cortex, ultimately resulting in the death of the patient. Well-defined risk factors for glioblastoma include radiation exposure and certain genetic syndromes. 21Several molecular and genomic datasets have recently been generated that have allowed identification of at least 4 subtypes of glioblastoma: classical, mesenchymal, proneural, and neural.14 Previous studies in glioblastoma geabbreviatioNs FBS = fetal bovine serum; HCC = hepatocellular carcinoma; HUVEC = human umbilical vein endothelial cell; lncRNA = long noncoding RNA; ncRNA = noncoding RNA; RT-qPCR = real-time quantitative reverse transcription polymerase chain reaction; SD = standard deviation. 3 Department of Respiratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing; and 4 Department of Oncology, The Second Affiliated Hospital of Suzhou University, Suzhou, China obJective Increased levels of H19 long noncoding RNA (lncRNA) have been observed in many cancers, suggesting that overexpression of H19 may be important in the development of carcinogenesis. However, the role of H19 in human glioblastoma is still unclear. The object of this study was to examine the level of H19 in glioblastoma samples and investigate the role of H19 in glioblastoma carcinogenesis. methods Glioblastoma and nontumor brain tissue specimens were obtained from tissue obtained during tumor resection in 30 patients with glioblastoma. The level of H19 lncRNA was detected by real-time quantitative reverse transcription polymerase chain reaction. The role of H19 in invasion, angiogenesis, and stemness of glioblastoma cells was then investigated using commercially produced cell lines (U87 and U373). The effects of H19 overexpression on glioblastoma cell invasion and angiogenesis were detected by in vitro Matrigel invasion and endothelial tube formation assay. The effects of H19 on glioblastoma cell stemness and tumorigenicity were investigated by neurosphere formation and an in vivo murine xenograft model. results The authors found that H19 is significantly overexpressed in glioblastoma tissues, and the level of expression was associated with patient survival. In the subsequent investigations, the authors found that overexpression of H19 promotes glioblastoma cell invasion and angiogenesis in vitro. Interestingly, H19 was also significantly overexpressed in CD133 + glioblastoma cells, and overexpression of H19 was associated with increased neurosphere formation of glioblastoma cells. Finally, stable overexpression of H19 was associated with increased tumor growth in the murine xenograft model. coNclusioNs The results of this study suggest that increased expression of H19 lncRNA promotes invasion, angiogenesis, stemness, and tumorigenicity of glioblastoma cells. Taken together, the...

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Section: Discussionmentioning

confidence: 88%

Increased level of H19 long noncoding RNA promotes invasion, angiogenesis, and stemness of glioblastoma cells

Jiang

Yan

et al. 2016

JNS

155

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“…Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor type with multiple genetic and epigenetic alterations ( 1 ). Sorafenib, standard of care for patients with advanced HCC in many countries, slows the growth of advanced liver cancers and increases patient survival by an average of 3 months ( 2,3 ).…”

Section: Introductionmentioning

confidence: 99%

First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway

et al. 2015

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Aberrant signaling through the fi broblast growth factor 19 (FGF19)/fi broblast growth factor receptor 4 (FGFR 4) signaling complex has been shown to cause hepatocellular carcinoma (HCC) in mice and has been implicated to play a similar role in humans. We have developed BLU9931, a potent and irreversible small-molecule inhibitor of FGFR4, as a targeted therapy to treat patients with HCC whose tumors have an activated FGFR4 signaling pathway. BLU9931 is exquisitely selective for FGFR4 versus other FGFR family members and all other kinases. BLU9931 shows remarkable antitumor activity in mice bearing an HCC tumor xenograft that overexpresses FGF19 due to amplifi cation as well as a liver tumor xenograft that overexpresses FGF19 mRNA but lacks FGF19 amplifi cation. Approximately one third of patients with HCC whose tumors express FGF19 together with FGFR4 and its coreceptor klotho β ( KLB ) could potentially respond to treatment with an FGFR4 inhibitor. These fi ndings are the fi rst demonstration of a therapeutic strategy that targets a subset of patients with HCC. SIGNIFICANCE:This article documents the discovery of BLU9931, a novel irreversible kinase inhibitor that specifi cally targets FGFR4 while sparing all other FGFR paralogs and demonstrates exquisite kinome selectivity. BLU9931 is effi cacious in tumors with an intact FGFR4 signaling pathway that includes FGF19, FGFR4, and KLB. BLU9931 is the fi rst FGFR4-selective molecule for the treatment of patients with HCC with aberrant FGFR4 signaling. Cancer Discov; 5(4);

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“…Especially in heterotopic model systems these are often artificially high (e.g., subcutaneous tumor implants). Second, a compromised liver function presents a major obstacle in clinical therapy trials, which are often jeopardized by increased drug toxicity (28).…”

Section: Liver Damagementioning

confidence: 99%

Model Matters: Differences in Orthotopic Rat Hepatocellular Carcinoma Physiology Determine Therapy Response to Sorafenib

Groß¹,

Steiger²,

Sayyed³

et al. 2015

Clinical Cancer Research

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Purpose: Preclinical model systems should faithfully reflect the complexity of the human pathology. In hepatocellular carcinoma (HCC), the tumor vasculature is of particular interest in diagnosis and therapy. By comparing two commonly applied preclinical model systems, diethylnitrosamine induced (DEN) and orthotopically implanted (McA) rat HCC, we aimed to measure tumor biology noninvasively and identify differences between the models.Experimental Design: DEN and McA tumor development was monitored by MRI and PET. A slice-based correlation of imaging and histopathology was performed. Array CGH analyses were applied to determine genetic heterogeneity. Therapy response to sorafenib was tested in DEN and McA tumors.Results: Histologically and biochemically confirmed liver damage resulted in increased 18 F-fluorodeoxyglucose (FDG) PET uptake and perfusion in DEN animals only. DEN tumors exhibited G1-3 grading compared with uniform G3 grading of McA tumors. Array comparative genomic hybridization revealed a highly variable chromosomal aberration pattern in DEN tumors. Heterogeneity of DEN tumors was reflected in more variable imaging parameter values. DEN tumors exhibited lower mean growth rates and FDG uptake and higher diffusion and perfusion values compared with McA tumors. To test the significance of these differences, the multikinase inhibitor sorafenib was administered, resulting in reduced volume growth kinetics and perfusion in the DEN group only.Conclusions: This work depicts the feasibility and importance of in depth preclinical tumor model characterization and suggests the DEN model as a promising model system of multifocal nodular HCC in future therapy studies.

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HCC therapies—lessons learned

Cited by 130 publications

References 37 publications

Increased level of H19 long noncoding RNA promotes invasion, angiogenesis, and stemness of glioblastoma cells

Increased level of H19 long noncoding RNA promotes invasion, angiogenesis, and stemness of glioblastoma cells

First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway

Model Matters: Differences in Orthotopic Rat Hepatocellular Carcinoma Physiology Determine Therapy Response to Sorafenib

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