Abstract 306: The efficacy of the combined treatment of 150 KHz tumor treating fields (TTFields) and Sorafenib in hepatocellular carcinoma in vitro and in vivo

2019 ◽  
Author(s):  
Tali Voloshin ◽  
Shiri Davidi ◽  
Catherine Tempel-Brami ◽  
Mijal Munster ◽  
Karnit Gotlib ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Combined Treatment ◽  
Tumor Treating Fields

In vitro and in vivo efficacy and safety of tumor treating fields (TTFields) and sorafenib combination in hepatocellular carcinoma.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 551-551
Author(s):  
Shiri Davidi ◽  
Catherine Tempel-Brami ◽  
Mijal Munster ◽  
Karnit Gotlib ◽  
Einav Zeevi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Treatment Group ◽  
Combination Treatment ◽  
Combined Treatment ◽  
Efficacy And Safety ◽  
Tumor Treating Fields ◽  
Clonogenic Potential ◽  
Hcc Cells

551 Background: Hepatocellular carcinoma (HCC) is a leading global cause of cancer-related mortality. Sorafenib (oral multikinase inhibitor) is approved in patients with advanced HCC, yet survival benefit is limited. Tumor Treating Fields (TTFields) are an effective, anti-neoplastic treatment modality delivered via noninvasive, low intensity (1-3 V/cm), intermediate frequency (100-500 kHz), alternating electric fields. The study aim was to explore in vitro and in vivo effects of TTFields alone and combined with sorafenib for HCC treatment. Methods: HCC (HepG2 and Huh-7D12) cells were TTFields treated with at frequencies of 100-400 kHz for 72 hr using the inovitro system. Efficacy of TTFields and sorafenib combined treatment was tested at optimal frequency with various sorafenib concentrations. Cell counts, apoptosis induction, and clonogenic potential were determined. Healthy rats were used to assess safety of TTFields applied to the abdomen. N1S1 HCC cells were injected into the left hepatic lobe of Sprague Dawley rat; after 1 week, TTFields (1.2 V/cm) and sorafenib (10 mg/kg) were applied for 6 days. Tumor growth was evaluated using MRI. Results: The optimal TTFields frequency was 150 kHz in HepG2 and Huh-7D12 HCC cells. TTFields 150 kHz treatment (1.0 - 1.7 V/cm, 72 hr) led to cell count reductions (53-55%) and further decreases in clonogenic potential (65-69%). TTFields and sorafenib combination treatment led to a significant reduction in cell count (2-way ANOVA, P < 0.05) vs either treatment alone. Also, tumor growth was significantly reduced in the combined treatment group vs the control group (student t test, P < 0.01). Tumor volume (fold increase) in the combination treatment group (1.6) was significantly lower vs control (5.9, P < 0.0001), TTFields alone (3.3, P < 0.01), and sorafenib alone (2.3, P < 0.05) groups. Safety studies did not reveal any TTFields related adverse events with delivery to the rat abdomen. Conclusions: In vitro and in vivo data demonstrated efficacy and safety of TTFields in HCC; and improved efficacy in combination with sorafenib. A phase 2 study (HEPANOVA; NCT03606590) will explore the clinical potential of TTFields 150 kHz plus sorafenib.

scholarly journals Radiosensitisation of Hepatocellular Carcinoma Cells by Vandetanib

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1878 ◽  
Author(s):  
Sami Znati ◽  
Rebecca Carter ◽  
Marcos Vasquez ◽  
Adam Westhorpe ◽  
Hassan Shahbakhti ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Combination Therapy ◽  
Cell Lines ◽  
Radiation Treatment ◽  
Combined Treatment ◽  
New Combination ◽  
Migration And Invasion ◽  
Syngeneic Mouse Model

Hepatocellular Carcinoma (HCC) is increasing in incidence worldwide and requires new approaches to therapy. The combination of anti-angiogenic drug therapy and radiotherapy is one promising new approach. The anti-angiogenic drug vandetanib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and RET proto-oncogene with radio-enhancement potential. To explore the benefit of combined vandetanib and radiotherapy treatment for HCC, we studied outcomes following combined treatment in pre-clinical models. Methods: Vandetanib and radiation treatment were combined in HCC cell lines grown in vitro and in vivo. In addition to 2D migration and clonogenic assays, the combination was studied in 3D spheroids and a syngeneic mouse model of HCC. Results: Vandetanib IC 50 s were measured in 20 cell lines and the drug was found to significantly enhance radiation cell kill and to inhibit both cell migration and invasion in vitro. In vivo, combination therapy significantly reduced cancer growth and improved overall survival, an effect that persisted for the duration of vandetanib treatment. Conclusion: In 2D and 3D studies in vitro and in a syngeneic model in vivo, the combination of vandetanib plus radiotherapy was more efficacious than either treatment alone. This new combination therapy for HCC merits evaluation in clinical trials.

The combined treatment of 150 kHz tumor treating fields (TTFields) and sorafenib inhibits hepatocellular carcinoma in vitro and in vivo.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15653-e15653 ◽  
Author(s):  
Uri Weinberg ◽  
Shiri Davidi ◽  
Catherine Tempel- Brami ◽  
Mijal Munster ◽  
Karnit Gotlib ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Combined Treatment ◽  
Control Group ◽  
Multikinase Inhibitor ◽  
Tumor Treating Fields ◽  
Cell Counts ◽  
Drug Concentrations ◽  
Clonogenic Potential ◽  
Hcc Cells

e15653 Background: Hepatocellular carcinoma (HCC) is the third cause of cancer related mortality and the primary cause of cancer death. Tumor Treating Fields (TTFields) therapy is an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. Sorafenib, an oral multikinase inhibitor is approved for patients with advanced HCC, yet its survival benefit is still limited. In this work we explored the potential of the use of TTFields alone and in combination with Sorafenib as a treatment for HCC. Methods: HepG2 and Huh-7D12 cells were treated with various TTFields frequencies for 72 hours using the inovitro system. Efficacy of the combined treatment of TTFields and Sorafenib (36-3000 nM) was tested by applying TTFields at the optimal frequency together with various drug concentrations. Cell counts, induction of apoptosis, cell cycle and clonogenic potential were determined. TTFields (1.2 V/cm) and Sorafenib (10 mg/kg) were applied for 6 days to rats injected to the liver with N1S1 HCC cells. Tumor growth was followed using MRI. Results: The optimal TTFields frequency was 150 kHz for both cell lines. TTFields application (1.0 - 1.7 V/cm, 72 hours) at 150 kHz led to 36-40% reduction in cell counts and to additional reduction of over 70% in the clonogenic potential. The combined treatment of TTFields and Sorafenib led to a significant reduction in the number of cells (p < 0.001) as compared to each treatment alone. The averaged tumor volume fold increase of the combination treatment group was significantly lower than the one observed in the: control group, the TTFields group and the Sorafenib group. Conclusions: The results presented in this work demonstrate that TTFields can be an effective treatment against HCC cells and that the combination with Sorafenib may further enhance treatment efficacy.

scholarly journals Cabozantinib-based combination therapy for the treatment of hepatocellular carcinoma

Gut ◽  
2020 ◽  
pp. gutjnl-2020-320716
Author(s):  
Runze Shang ◽  
Xinhua Song ◽  
Pan Wang ◽  
Yi Zhou ◽  
Xinjun Lu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Therapeutic Efficacy ◽  
Checkpoint Inhibitor ◽  
Primary Liver Cancer ◽  
Combined Treatment ◽  
Tumour Regression ◽  
Liver Tumours ◽  
Multikinase Inhibitor

ObjectiveHepatocellular carcinoma (HCC) is the most common type of primary liver cancer with limited treatment options. Cabozantinib, an orally bioavailable multikinase inhibitor is now approved by Food and Drug Administration (FDA) for HCC patients. We evaluated the therapeutic efficacy of cabozantinib, either alone or in combination, in vitro and in vivo.DesignHuman HCC cell lines and HCC mouse models were used to assess the therapeutic efficacy and targeted molecular pathways of cabozantinib, either alone or in combination with the pan-mTOR inhibitor MLN0128 or the checkpoint inhibitor anti-PD-L1 antibody.ResultsCabozantinib treatment led to stable disease in c-Met/β-catenin and Akt/c-Met mouse HCC while possessing limited efficacy on Akt/Ras and c-Myc liver tumours. Importantly, cabozantinib effectively inhibited c-MET and ERK activity, leading to decreased PKM2 and increased p21 expression in HCC cells and in c-Met/β-catenin and Akt/c-Met HCC. However, cabozantinib was ineffective in inhibiting the Akt/mTOR cascade. Intriguingly, a strong inhibition of angiogenesis by cabozantinib occurred regardless of the oncogenic drivers. However, cabozantinib had limited impact on other tumour microenvironment parameters, including tumour infiltrating T cells, and did not induce programmed death-ligand 1 (PD-L1) expression. Combining cabozantinib with MLN0128 led to tumour regression in c-Met/β-catenin mice. In contrast, combined treatment with cabozantinib and the checkpoint inhibitor anti-PD-L1 antibody did not provide any additional therapeutic benefit in the four mouse HCC models tested.Conclusionc-MET/ERK/p21/PKM2 cascade and VEGFR2-induced angiogenesis are the primary targets of cabozantinib in HCC treatment. Combination therapies with cabozantinib and mTOR inhibitors may be effective against human HCC.

scholarly journals Synergistic antitumor effect of resveratrol and sorafenib on hepatocellular carcinoma through PKA/AMPK/eEF2K pathway

2021 ◽  
Author(s):  
Meili Gao ◽  
Chun Deng ◽  
Fan Dang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Tumor Response ◽  
Therapeutic Potential ◽  
Combined Treatment ◽  
In Vivo Studies ◽  
Antitumor Effects ◽  
Protein Levels

Although sorafenib (Sor) is the only effective drug for hepatocellular carcinoma (HCC), its therapeutic potential to date is mainly limited to the low tumor response. This study was designed to explore whether resveratrol (Res) could potentiate the anticancerous activity of Sor. We used HepG2 and Huh7 HCC cell lines and BALB/c nude mice for in vitro and in vivo studies, respectively. The cultured cell lines and tumor induction in the mice were treated with different concentrations of Res and Sor alone, and the combination of Res and Sor to observe the antitumor effects. Significant inhibitory effects were observed in the combined treatment of Res and Sor compared to Res and Sor alone treatments both in vitro and in vivo as demonstrated by significantly high number of S phase cells and apoptotic cells. Moreover, these findings were accompanied by the reduction of CDK2, CDC25A, PKA, p-AMPK, and eEF2K protein levels and the increment of cyclin A, cleavage caspase-3, caspase-8, and caspase-9 protein levels. The combinational treatment exhibited more significant anticancerous effect than the Res and Sor alone treatments in mice-bearing HepG2 xenograft. Overall, our results suggest that PKA/AMPK/eEF2K pathway is involved in the synergistic anticancerous activity of Res and Sor combination treatment in HCC cells. Thus, Res and Sor combination therapy may be promising in increasing the tumor response of Sor in the future.

scholarly journals Combined Treatment with MEK and mTOR Inhibitors is Effective in In Vitro and In Vivo Models of Hepatocellular Carcinoma

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 930 ◽  
Author(s):  
Xianqiong Liu ◽  
Junjie Hu ◽  
Xinhua Song ◽  
Kirsten Utpatel ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Combined Treatment ◽  
Mtor Inhibitors ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mtor Inhibition ◽  
In Vivo Models

Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer histotype, characterized by high biological aggressiveness and scarce treatment options. Recently, we have established a clinically relevant murine HCC model by co-expressing activated forms of v-akt murine thymoma viral oncogene homolog (AKT) and oncogene c-mesenchymal-epithelial transition (c-Met) proto-oncogenes in the mouse liver via hydrodynamic tail vein injection (AKT/c-MET mice). Tumor cells from these mice demonstrated high activity of the AKT/ mammalian target of rapamycin (mTOR) and Ras/ Mitogen-activated protein kinase (MAPK) signaling cascades, two pathways frequently co-induced in human HCC. Methods: Here, we investigated the therapeutic efficacy of sorafenib, regorafenib, the MEK inhibitor PD901 as well as the pan-mTOR inhibitor MLN0128 in the AKT/c-Met preclinical HCC model. Results: In these mice, neither sorafenib nor regorafenib demonstrated any efficacy. In contrast, administration of PD901 inhibited cell cycle progression of HCC cells in vitro. Combined PD901 and MLN0128 administration resulted in a pronounced growth constraint of HCC cell lines. In vivo, treatment with PD901 or MLN0128 alone moderately slowed HCC growth in AKT/c-MET mice. Importantly, the simultaneous administration of the two drugs led to a stable disease with limited tumor progression in mice. Mechanistically, combined mitogen-activated extracellular signal-regulated kinase (MEK) and mTOR inhibition resulted in a stronger cell cycle inhibition and growth arrest both in vitro and in vivo. Conclusions: Our study indicates that combination of MEK and mTOR inhibitors might represent an effective therapeutic approach against human HCC.

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