Tyrosine kinase inhibitors crossing the blood brain barrier
1 Background
Among non-small cell lung cancer patients, 24-44% of patients develop brain metastases during the course of their disease. The risk of brain metastasis is increased for patients with mutated Epidermal Growth Factor Receptor (EGFR) positive tumors. Various clinical trials have been conducted to elucidate the effectiveness of tyrosine kinase inhibition in the management of brain metastases. Tumor response has been indicated, but generally it is considered that the clinically administered tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib, and afatinib have poor biopharmaceutical properties for penetrating the blood-brain barrier. The TKIs Osimertinib and Brigatinib are known for being able to penetrate the blood-brain barrier. It is therefore hoped that PET tracers based on these structures might be able to target brain metastases caused by mutated EGFR, enabling a non-invasive tool for the diagnosis and monitoring the treatment response of the tumors.
This hypothesis will be examined in the established human metastasis model for studying metastatic progression, where human metastatic tumor cells are injected into the left cardiac ventricle of immunodeficient mice.
Detailed characterization of the blood-brain barrier (BBB) has been performed in the tumor model. The model and knowledge is currently shared with several other research groups (in UK, Germany, USA, The Netherlands).
2. Aim of the research
The aim of this project is to bring our research into a phase 1 clinical trial on cancer metastasis patients. The current application thus describes a set of important experiments, in order to achieve this.
3. Expected harm to the animals
Moderate harm due to intracardial injection.
The injected tracer is not a hazardous substance or mixture according to regulation (EC) No 1272/2008.
4. Expected benefit for science and society
If successful, we hope to achieve a new and better diagnosis tool for cancer patients with metastatic spread to the brain.
5. How many and kind of animals to be used
We plan to use up to a total of 10 nod/scid mice in our experiments.
6. How the demand on RRR is to be achieved
We need to use animal models in our research, as in vitro models do not reflect the 3d structural behavior and physiological conditions in animals, and these conditions are crucial for metastatic spread of cancers in patients. Therefore, we are of the opinion that in vitro experiments are not sufficient to obtain our aim, which is to bring new treatment into the clinic.
Among non-small cell lung cancer patients, 24-44% of patients develop brain metastases during the course of their disease. The risk of brain metastasis is increased for patients with mutated Epidermal Growth Factor Receptor (EGFR) positive tumors. Various clinical trials have been conducted to elucidate the effectiveness of tyrosine kinase inhibition in the management of brain metastases. Tumor response has been indicated, but generally it is considered that the clinically administered tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib, and afatinib have poor biopharmaceutical properties for penetrating the blood-brain barrier. The TKIs Osimertinib and Brigatinib are known for being able to penetrate the blood-brain barrier. It is therefore hoped that PET tracers based on these structures might be able to target brain metastases caused by mutated EGFR, enabling a non-invasive tool for the diagnosis and monitoring the treatment response of the tumors.
This hypothesis will be examined in the established human metastasis model for studying metastatic progression, where human metastatic tumor cells are injected into the left cardiac ventricle of immunodeficient mice.
Detailed characterization of the blood-brain barrier (BBB) has been performed in the tumor model. The model and knowledge is currently shared with several other research groups (in UK, Germany, USA, The Netherlands).
2. Aim of the research
The aim of this project is to bring our research into a phase 1 clinical trial on cancer metastasis patients. The current application thus describes a set of important experiments, in order to achieve this.
3. Expected harm to the animals
Moderate harm due to intracardial injection.
The injected tracer is not a hazardous substance or mixture according to regulation (EC) No 1272/2008.
4. Expected benefit for science and society
If successful, we hope to achieve a new and better diagnosis tool for cancer patients with metastatic spread to the brain.
5. How many and kind of animals to be used
We plan to use up to a total of 10 nod/scid mice in our experiments.
6. How the demand on RRR is to be achieved
We need to use animal models in our research, as in vitro models do not reflect the 3d structural behavior and physiological conditions in animals, and these conditions are crucial for metastatic spread of cancers in patients. Therefore, we are of the opinion that in vitro experiments are not sufficient to obtain our aim, which is to bring new treatment into the clinic.