Treatment of glioblastoma using Bevacizumab and Albendazole
Background
Glioblastoma multiforme (GBM) is a malignant brain tumour with a dismal prognosis. Current treatments are largely ineffective. Despite being a highly vascularized tumour, two phase III clinical trials failed to demonstrate any survival benefit from bevacizumab, an antibody targeting VEGF. We have previously shown that up-regulation of Hif1a is a key driver of resistance to VEGF targeted therapy. As such, combining VEGF targeted therapy with inhibition of Hif1a might be an effective treatment approach. We have recently shown that Albendazole, an established antihelmetic, is a potent Hif1a inhibitor in-vitro.
Purpose
The aim of this project is to investigate the efficacy of Albendazole as mono therapy and in combination with bevacizumab in orthotopically implanted glioblastoma xenografts.
Expected harm to the animals
The investigational compounds are well tolerated, and already approved for use on human patients. Implantation and imaging will inflict mild to moderate harm to the animals, while tumor growth in the brain can potentially inflict moderate harm to the animals.
Expected benefit for science and society
Improved survival and quality of life for patients with glioblastoma.
How many and kind of animals to be used
40 nod/scid mice.
How the demand on RRR is to be achieved
Replacement: To establish whether a new drug combination is safe and effective in-vivo, there is a need to use animal models before entering human clinical trials. In particular, in-vitro models do not reflect the 3D microenvironment and physiological conditions in animals. Therefore, in vitro experiments are not sufficient to assess the treatment efficacy.
Refinement: The surgical procedures will cause mild harm to the animals. We use two trained researchers during the implantations, one responsible for the implantations, and the other responsible for animal care. The animals are placed onto a heating pad, and we use analgesics, to make the implantation procedure as indulgent as possible. During imaging, two trained persons are present, one to prepare and monitor the animals, and the other to operate the imaging instrumentation. Heating is also used. The imaging procedures do not cause any harm to the animals.
Regarding tumor development, the animals are monitored daily by trained people, and weighed twice/week. Regular imaging as described is important, as this will reveal tumor burden before detecting any symptoms in animal behavior. The last two weeks before sacrifice, the animals show progressive signs of discomfort, and analgesics will be considered.
Reduction: We are using microscope-guided implantation of patient-derived glioblastoma cells into the brains of mice, which increases our success rate. Thus, we can cut down the number of animals in each experimental group with 2 animals (from 12 to 10 animals).
Glioblastoma multiforme (GBM) is a malignant brain tumour with a dismal prognosis. Current treatments are largely ineffective. Despite being a highly vascularized tumour, two phase III clinical trials failed to demonstrate any survival benefit from bevacizumab, an antibody targeting VEGF. We have previously shown that up-regulation of Hif1a is a key driver of resistance to VEGF targeted therapy. As such, combining VEGF targeted therapy with inhibition of Hif1a might be an effective treatment approach. We have recently shown that Albendazole, an established antihelmetic, is a potent Hif1a inhibitor in-vitro.
Purpose
The aim of this project is to investigate the efficacy of Albendazole as mono therapy and in combination with bevacizumab in orthotopically implanted glioblastoma xenografts.
Expected harm to the animals
The investigational compounds are well tolerated, and already approved for use on human patients. Implantation and imaging will inflict mild to moderate harm to the animals, while tumor growth in the brain can potentially inflict moderate harm to the animals.
Expected benefit for science and society
Improved survival and quality of life for patients with glioblastoma.
How many and kind of animals to be used
40 nod/scid mice.
How the demand on RRR is to be achieved
Replacement: To establish whether a new drug combination is safe and effective in-vivo, there is a need to use animal models before entering human clinical trials. In particular, in-vitro models do not reflect the 3D microenvironment and physiological conditions in animals. Therefore, in vitro experiments are not sufficient to assess the treatment efficacy.
Refinement: The surgical procedures will cause mild harm to the animals. We use two trained researchers during the implantations, one responsible for the implantations, and the other responsible for animal care. The animals are placed onto a heating pad, and we use analgesics, to make the implantation procedure as indulgent as possible. During imaging, two trained persons are present, one to prepare and monitor the animals, and the other to operate the imaging instrumentation. Heating is also used. The imaging procedures do not cause any harm to the animals.
Regarding tumor development, the animals are monitored daily by trained people, and weighed twice/week. Regular imaging as described is important, as this will reveal tumor burden before detecting any symptoms in animal behavior. The last two weeks before sacrifice, the animals show progressive signs of discomfort, and analgesics will be considered.
Reduction: We are using microscope-guided implantation of patient-derived glioblastoma cells into the brains of mice, which increases our success rate. Thus, we can cut down the number of animals in each experimental group with 2 animals (from 12 to 10 animals).