Abstract
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 ICs 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.
Highlights
The risk of liver cancer has been steadily increasing since the end of the 20th century [1], accounting for more than 8% of cancer-related deaths and 5% of cancer occurrence worldwide [2].Hepatocellular carcinoma (HCC) is by far the most common liver cancer, accounting for 70–85% of Cancers 2020, 12, 1878; doi:10.3390/cancers12071878 www.mdpi.com/journal/cancersCancers 2020, 12, 1878 total liver cancer occurrence [3], whereas Intrahepatic and Extrahepatic Cholangiocarcinoma (ICC and ECC respectively) occur less frequently
One approach to improving Stereotactic BodyRadiation Therapy (SBRT) outcomes for HCC patients is the use of radiosensitisers [7], drugs which combine with radiotherapy to enhance the anti-cancer effect
The expression of vascular endothelial growth factor receptor-2 (VEGFR-2) in human and murine cell lines was measured with western blotting to assess functional VEGFR-2 signalling and susceptibility to vandetanib and similar tyrosine kinase inhibitor (TKI), both of which have implications for cancer growth and vandetanib treatment (Figure 1)
Summary
The risk of liver cancer has been steadily increasing since the end of the 20th century [1], accounting for more than 8% of cancer-related deaths and 5% of cancer occurrence worldwide [2].Hepatocellular carcinoma (HCC) is by far the most common liver cancer, accounting for 70–85% of Cancers 2020, 12, 1878; doi:10.3390/cancers12071878 www.mdpi.com/journal/cancersCancers 2020, 12, 1878 total liver cancer occurrence [3], whereas Intrahepatic and Extrahepatic Cholangiocarcinoma (ICC and ECC respectively) occur less frequently. Patients with HCC are treated with curative resection if possible, or other therapies depending on staging [4,5]. One approach to improving SBRT outcomes for HCC patients is the use of radiosensitisers [7], drugs which combine with radiotherapy to enhance the anti-cancer effect. Radiosensitisers can act via intrinsic methods by directly impairing cell function and ability to survive radiation-induced damage, as is the case with platinum-based DNA chelators [8,9,10,11] and PARP inhibitors [12], both of which impair cellular DNA repair and replication. Other radiosensitisers act extrinsically by placing a toxic burden on the cell prior to radiation, as is the case with PI-103 and mTOR blockade which disrupt autophagy, leading to cell death [13]. Vandetanib is a substrate-specific tyrosine kinase inhibitor (TKI), with ten-fold selectivity for vascular endothelial growth factor receptor-2
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
