scholarly journals Bevacizumab Augments the Antitumor Efficacy of Infigratinib in Hepatocellular Carcinoma

2020 ◽  
Vol 21 (24) ◽  
pp. 9405
Author(s):  
Thi Bich Uyen Le ◽  
Thanh Chung Vu ◽  
Rebecca Zhi Wen Ho ◽  
Aldo Prawira ◽  
Lingzhi Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Signaling Pathways ◽  
De Novo ◽  
Angiogenesis Inhibitor ◽  
Vegf Receptor ◽  
Targeted Agents ◽  
Therapeutic Benefits ◽  
Potential Biomarker ◽  
Fgfr Signaling

The fibroblast growth factor (FGF) signaling cascade is one of the key signaling pathways in hepatocellular carcinoma (HCC). FGF has been shown to augment vascular endothelial growth factor (VEGF)-mediated HCC development and angiogenesis, as well as to potentially lead to resistance to VEGF/VEGF receptor (VEGFR)-targeted agents. Thus, novel agents targeting FGF/FGF receptor (FGFR) signaling may enhance and/or overcome de novo or acquired resistance to VEGF-targeted agents in HCC. Mice bearing high- and low-FGFR tumors were treated with Infigratinib (i.e., a pan-FGFR kinase inhibitor) and/or Bevacizumab (i.e., an angiogenesis inhibitor). The antitumor activity of both agents was assessed individually or in combination. Tumor vasculature, intratumoral hypoxia, and downstream targets of FGFR signaling pathways were also investigated. Infigratinib, when combined with Bevacizumab, exerted a synergistic inhibitory effect on tumor growth, invasion, and lung metastasis, and it significantly improved the overall survival of mice bearing FGFR-dependent HCC. Infigratinib/Bevacizumab promoted apoptosis, inhibited cell proliferation concomitant with upregulation of p27, and reduction in the expression of FGFR2-4, p-FRS-2, p-ERK1/2, p-p70S6K/4EBP1, Cdc25C, survivin, p-Cdc2, and p-Rb. Combining Infigratinib/Bevacizumab may provide therapeutic benefits for a subpopulation of HCC patients with FGFR-dependent tumors. A high level of FGFR-2/3 may serve as a potential biomarker for patient selection to Infigratinib/Bevacizumab.

scholarly journals Perforation of the Small Intestine after Introduction of Lenvatinib in a Patient with Advanced Hepatocellular Carcinoma

2020 ◽  
Vol 14 (1) ◽  
pp. 63-69 ◽  
Author(s):  
Naomi Suzuki ◽  
Kazuto Tajiri ◽  
Yuka Futsukaichi ◽  
Shinichi Tanaka ◽  
Aiko Murayama ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Small Intestine ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Vegf Receptor ◽  
Advanced Hepatocellular Carcinoma ◽  
Vascular Endothelial ◽  
First Line ◽  
Endothelial Growth Factor ◽  
Line Standard

Lenvatinib is a first-line standard treatment for advanced hepatocellular carcinoma (HCC) with better anti-tumor effects than sorafenib, as shown by greater inhibition of the kinases of fibroblast growth factor receptor and vascular endothelial growth factor (VEGF) receptor. This report describes a patient with advanced HCC who experienced perforation of the small intestine 1 month after starting the treatment with lenvatinib. This patient likely had partial necrosis of a metastasis to the small intestine before starting lenvatinib treatment, with subsequent ischemic changes leading to perforation of the small intestine. Although metastasis of HCC to the small intestine is rare, patients with these metastases should be regarded as being at risk for perforation during lenvatinib treatment.

scholarly journals Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

2018 ◽  
Vol 12 (9) ◽  
pp. 1480-1497 ◽  
Author(s):  
Xuejie Min ◽  
Jun Wen ◽  
Li Zhao ◽  
Kaiying Wang ◽  
Qingli Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
De Novo ◽  
De Novo Lipogenesis

Involvement of Egr-1 in HGF-induced elevation of the human 5α-R1 gene in human hepatocellular carcinoma cells

2008 ◽  
Vol 411 (2) ◽  
pp. 379-386 ◽  
Author(s):  
Caixia Rui ◽  
Changyan Li ◽  
WangXiang Xu ◽  
Yiqun Zhan ◽  
Yonghui Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
Mrna Expression ◽  
Transcriptional Activation ◽  
De Novo ◽  
The Body ◽  
Carcinoma Cells ◽  
Mobility Shift ◽  
Hepatocellular Carcinoma Cells ◽  
R1 Gene

Steroid 5α-reductase 1 (5α-R1), a key enzyme in the conversion of steroids into their respective 5α-reduced derivatives, plays a key role in some hormone-dependent tumours and is abundant in the liver, although it is also widely distributed throughout the body. HGF (hepatocyte growth factor) is a pleiotropic cytokine/growth factor involved in the progression of hepatocellular carcinoma. In the present paper, we report the stimulatory effect of HGF on human 5α-R1 transcription in hepatocellular carcinoma cells. Pre-treatment with actinomycin D or cycloheximide blocked the up-regulation of 5α-R1 mRNA expression by HGF, indicating that the increased level of 5α-R1 mRNA expression is regulated by transcriptional activation and was dependent on de novo protein synthesis. Functional analysis of the 5′-flanking region of the 5α-R1 gene by transfection analysis showed that the −79 to −50 region functioned as the HGF-responsive region. Mutagenesis and electrophoretic mobility-shift assays demonstrated that induction of 5a-R1 by HGF is mediated by an Egr-1 (early growth-response gene 1)-binding site at −60/−54. In addition, overexpression of Egr-1 was sufficient to transactivate 5α-R1 promoter activity, and knockdown of Egr-1 with gene-specific small interfering RNA resulted in inhibition of HGF-induced up-regulation of endogenous 5α-R1 expression. These data provide the first evidence that HGF stimulates 5α-R1 expression through up-regulation of the transcription factor Egr-1, thus suggesting the possibility that regulation of steroid metabolism by HGF represents a mechanism for high risk of hepatocellular carcinogenesis in males.

scholarly journals New and Promising Targeted Therapies in First and Second-Line Settings

2021 ◽  
pp. 277-296
Author(s):  
Dylan F. Roden ◽  
Jennifer M. Johnson ◽  
Petr Szturz ◽  
Paolo Bossi ◽  
Athanassios Argiris
Keyword(s):  
Growth Factor ◽  
Targeted Therapies ◽  
Checkpoint Inhibitors ◽  
Growth Factor Receptor ◽  
Clinical Trial Data ◽  
Treatment Modalities ◽  
Vegf Receptor ◽  
Targeted Agents ◽  
Repair Mechanisms ◽  
Cycle Regulation

AbstractDeeper understanding of the molecular pathogenesis of malignancies, including head and neck squamous cell carcinoma (HNSCC), has led to the investigation of several novel targeted therapies. These therapeutic approaches may eventually replace or complement existing treatment modalities, such as surgery, radiation therapy, and traditional cytotoxic chemotherapy. Epidermal growth factor receptor (EGFR) inhibitors, and specifically cetuximab, are as of now the only class of targeted agents, excluding immune checkpoint inhibitors, with approval in the treatment of HNSCC. Beyond EGFR inhibition, novel therapies under evaluation are directed against vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR), PI3K/AKT/mTOR pathway, cell cycle regulation (for example, cyclin dependent kinases 4 and 6), HRAS, DNA repair mechanisms, and others. Development of new therapies has to take into consideration the complexity of solid tumors and their heterogeneity. Multitargeted combination therapy approaches may be required in certain cases in order to maximize antitumor effect. Ways to individualize treatment using validated biomarkers are likely to improve outcomes. We review the most relevant molecular targets in HNSCC and provide updates on clinical trial data with promising new targeted agents.

scholarly journals A Network Map of FGF-1/FGFR Signaling System

2014 ◽  
Vol 2014 ◽  
pp. 1-16 ◽  
Author(s):  
Rajesh Raju ◽  
Shyam Mohan Palapetta ◽  
Varot K. Sandhya ◽  
Apeksha Sahu ◽  
Abbas Alipoor ◽  
...  
Keyword(s):  
Growth Factor ◽  
Signaling Pathways ◽  
Data Exchange ◽  
Cell Types ◽  
Signaling System ◽  
Standard Data ◽  
Physiological Processes ◽  
Pathway Data ◽  
Fgfr Signaling ◽  
Different Cell Types

Fibroblast growth factor-1 (FGF-1) is a well characterized growth factor among the 22 members of the FGF superfamily in humans. It binds to all the four known FGF receptors and regulates a plethora of functions including cell growth, proliferation, migration, differentiation, and survival in different cell types. FGF-1 is involved in the regulation of diverse physiological processes such as development, angiogenesis, wound healing, adipogenesis, and neurogenesis. Deregulation of FGF-1 signaling is not only implicated in tumorigenesis but also is associated with tumor invasion and metastasis. Given the biomedical significance of FGFs and the fact that individual FGFs have different roles in diverse physiological processes, the analysis of signaling pathways induced by the binding of specific FGFs to their cognate receptors demands more focused efforts. Currently, there are no resources in the public domain that facilitate the analysis of signaling pathways induced by individual FGFs in the FGF/FGFR signaling system. Towards this, we have developed a resource of signaling reactions triggered by FGF-1/FGFR system in various cell types/tissues. The pathway data and the reaction map are made available for download in different community standard data exchange formats through NetPath and NetSlim signaling pathway resources.

Phase I Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PTK787/ZK 222584 Administered Twice Daily in Patients With Advanced Cancer

2005 ◽  
Vol 23 (18) ◽  
pp. 4162-4171 ◽  
Author(s):  
Anne L. Thomas ◽  
Bruno Morgan ◽  
Mark A. Horsfield ◽  
Anthony Higginson ◽  
Andrea Kay ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Phase I ◽  
Single Agent ◽  
Angiogenesis Inhibitor ◽  
Biologically Active ◽  
Pharmacokinetic Data ◽  
Vegf Receptor ◽  
Dce Mri ◽  
Grade 3

Purpose PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting all known vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase, and the c-kit protein tyrosine kinase. In this phase I dose-escalating study, PTK/ZK was administered bid to exploit the theoretical advantage of maintaining constant drug levels above a threshold known from preclinical data to interfere with VEGF receptor signaling. Patients and Methods Forty-three patients with advanced cancers received single-agent PTK/ZK at doses of 150 to 1,000 mg orally bid. Assessments for safety and pharmacokinetics were performed. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used as a pharmacodynamic marker of response. Results At 1,000 mg bid, the dose-limiting toxicity of reversible grade 3 lightheadedness was observed. Dose-related grade 3 fatigue and vomiting were observed but these were not dose-limiting. Pharmacokinetic data confirmed that PTK/ZK exposure increased with increasing dose up to 500 mg bid and appeared to plateau at higher doses. A greater than 40% reduction in the DCE-MRI bidirectional transfer constant (Ki) at day 2 predicted for nonprogression of disease. Conclusion The maximum-tolerated oral dose of PTK/ZK is 750 mg orally bid. DCE-MRI and pharmacokinetic data indicate that PTK/ZK ≥ 1,000 mg total daily dose is the biologically active dose.

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