Establishment cancer models mimicking metastatic disease
I. The purpose of the experiment/project:
The purpose of this experiment is to establish several in vivo models mimicking metastatic disease for further use of these models for evaluation of targeted radiopharmaceuticals.
II. The expected adverse effects on the animals:
Adverse effects in this experiments are associated with surgical establishment of cancer metastasis and symptoms associated with site-specific metastasis and typically manifest as decline in general health, body weight reduction, reduction in activity level, changes in skin color. To mitigate these adverse effects, we will daily follow the mice well-being, applying the score scheme for assessment of animal well-being. Post-surgical adverse effects are post-surgical pain or infection. To mitigate these effect, we will use proper local and general analgesia and surgical zone disinfection to reduce the risk of infection.
III. The expected scientific benefits or benefits for society:
This experiment aims to select the optimal tumor model for evaluation of treatment effect on metastatic disease, following reduction and refinement principles. An optimal model has:
-little impact on mouse general health
-resembles the human disease in term of target expression, microenvironment and metastasis location
-small variations between animals, resulting in fewer animals used
This study will provide us with a toolbox of well characterized tumor models for future projects and new targets. The targeting radiopharmaceutical we aim to investigate in the future studies will offer a treatment option for patients currently lacking any treatment option in late stages of their metastatic disease.
IV. The number of animals and species:
In this study we aim to establish up to 10 models expressing different levels of different targets relevant for our targeting radiopharmaceuticals' projects. For each model we will perform an evaluation of the model with 3 mice, determining take rate, growth and target expression, followed by evaluation in the expansion cohort with 10 mice to review model heterogeneity and variation between mice. For each mode we would then need 13 mice, in total 13 mice x 10 models = 130 mice.
V. How will the requirements for 3R be accomplished by the experiment/project:
All the models considered to be established will undergo evaluation consisting of literature review to identify whether the cell line is suitable for the metastatic model, in vitro analysis such as target binding assays, in vitro efficacy etc. and project value evaluation. No models will be established unless necessary for biodistriburtion/efficacy studies. Information from model development studies will be used to find the optimal treatment initiation timing, growth rate and termination allowing to reduce the number of mice in efficacy study due to reduced variability. We will conduct a small trial for model evaluation, with 3 mice only to reduce the total number of mice per model. A second part of the evaluation will not be conducted if the model will show to be morbid and have to severe influence on animal health or show no tumor growth. Studies will be performed in collaboration with researches with great experience with such models.
The purpose of this experiment is to establish several in vivo models mimicking metastatic disease for further use of these models for evaluation of targeted radiopharmaceuticals.
II. The expected adverse effects on the animals:
Adverse effects in this experiments are associated with surgical establishment of cancer metastasis and symptoms associated with site-specific metastasis and typically manifest as decline in general health, body weight reduction, reduction in activity level, changes in skin color. To mitigate these adverse effects, we will daily follow the mice well-being, applying the score scheme for assessment of animal well-being. Post-surgical adverse effects are post-surgical pain or infection. To mitigate these effect, we will use proper local and general analgesia and surgical zone disinfection to reduce the risk of infection.
III. The expected scientific benefits or benefits for society:
This experiment aims to select the optimal tumor model for evaluation of treatment effect on metastatic disease, following reduction and refinement principles. An optimal model has:
-little impact on mouse general health
-resembles the human disease in term of target expression, microenvironment and metastasis location
-small variations between animals, resulting in fewer animals used
This study will provide us with a toolbox of well characterized tumor models for future projects and new targets. The targeting radiopharmaceutical we aim to investigate in the future studies will offer a treatment option for patients currently lacking any treatment option in late stages of their metastatic disease.
IV. The number of animals and species:
In this study we aim to establish up to 10 models expressing different levels of different targets relevant for our targeting radiopharmaceuticals' projects. For each model we will perform an evaluation of the model with 3 mice, determining take rate, growth and target expression, followed by evaluation in the expansion cohort with 10 mice to review model heterogeneity and variation between mice. For each mode we would then need 13 mice, in total 13 mice x 10 models = 130 mice.
V. How will the requirements for 3R be accomplished by the experiment/project:
All the models considered to be established will undergo evaluation consisting of literature review to identify whether the cell line is suitable for the metastatic model, in vitro analysis such as target binding assays, in vitro efficacy etc. and project value evaluation. No models will be established unless necessary for biodistriburtion/efficacy studies. Information from model development studies will be used to find the optimal treatment initiation timing, growth rate and termination allowing to reduce the number of mice in efficacy study due to reduced variability. We will conduct a small trial for model evaluation, with 3 mice only to reduce the total number of mice per model. A second part of the evaluation will not be conducted if the model will show to be morbid and have to severe influence on animal health or show no tumor growth. Studies will be performed in collaboration with researches with great experience with such models.