Journal Article

Increased therapeutic effect on medullary thyroid cancer using a combination of radiation and tyrosine kinase inhibitors

Montelius, Mikael, Ståhl, Ingun, Shubbar, Emman, Nilsson, Ola, Sandblom, Viktor, Spetz, Johan, Swanpalmer, John, Forssell-Aronsson, Eva

2020

Overview

Since patients with medullary thyroid cancer (MTC) often have metastatic disease at the time of diagnosis, the development of efficient systemic treatment options for MTC is important. Vandetanib and cabozantinib are two tyrosine kinase inhibitors (TKIs) that were recently approved by FDA and EMA for systemic treatment of metastatic MTC. Additionally, since MTC is of a neuroendocrine tumour type, treatment with radiolabelled somatostatin analogues (e.g. 177Lu-octreotate) is a valid option for patients with MTC. The aim of this study was to investigate the potentially increased therapeutic effect of combining radiation therapy with these TKIs for treatment of MTC in a mouse model. Nude mice carrying patient-derived MTC tumours (GOT2) were treated with external beam radiotherapy (EBRT) and/or one of the two TKIs vandetanib or cabozantinib. The tumour volume was determined and compared with that of mock-treated controls. The treatment doses were chosen to give a moderate effect as monotherapy to be able to detect any increased therapeutic effect from the combination therapy. At the end of follow-up, tumours were processed for immunohistochemical (IHC) analyses. The animals in the combination therapy groups showed the largest reduction in tumour volume and the longest time to tumour progression. Two weeks after start of treatment, the tumour volume for these mice was reduced by about 70-75% compared with controls. Furthermore, also EBRT and TKI monotherapy resulted in a clear anti-tumour effect with a reduced tumour growth compared with controls. The results show that an increased therapeutic effect could be achieved when irradiation is combined with TKIs for treatment of MTC. Future studies should evaluate the potential of using 177Lu-octreotate therapy in combination with TKIs in patients.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Anilides - pharmacology / Animals / Anticancer properties / Biology and Life Sciences / Biomedical engineering / Cabozantinib / Cancer / Cancer metastasis / Cancer patients / Cancer therapies / Carcinoma, Neuroendocrine - enzymology / Carcinoma, Neuroendocrine - pathology / Carcinoma, Neuroendocrine - therapy / Care and treatment / Chemoradiotherapy / Diseases / Drug approval / Drug dosages / Female / Future predictions / Health physics / Hospitals / Humans / Inhibitor drugs / Inhibitors / Irradiation / Kinases / Lutetium isotopes / Medical prognosis / Medicine and Health Sciences / Metastases / Metastasis / Mice / Mice, Inbred BALB C / Mice, Nude / Mutation / Neoplasm Proteins - antagonists & inhibitors / Neoplasm Proteins - metabolism / Neuroendocrine tumors / Patient outcomes / Patients / Phenols (Class of compounds) / Physics / Piperidines - pharmacology / Protein-tyrosine kinase / Protein-Tyrosine Kinases - antagonists & inhibitors / Protein-Tyrosine Kinases - metabolism / Pyridines - pharmacology / Quinazolines - pharmacology / Radiation / Radiation (Physics) / Radiation therapy / Radiotherapy / Research and Analysis Methods / Somatostatin / Targeted cancer therapy / Thyroid / Thyroid cancer / Thyroid diseases / Thyroid Neoplasms - enzymology / Thyroid Neoplasms - pathology / Thyroid Neoplasms - therapy / Time / Tumors / Tyrosine / Tyrosine kinase inhibitors / Vandetanib / Xenograft Model Antitumor Assays