Establishing patient derived xenograft (PDX) models for targeted treatment of metastatic endometrial cancer
Endometrial cancer is amongst the most common cancer types in women in western countries, and incidence is expected to rise due to higher life expectancy and increased overweight in the population. Women with metastatic endometrial cancer usually have poor prognosis, as traditional cytostatic drugs have moderate response rates and limited survival benefits. Individually tailored treatment of metastatic endometrial cancer based on molecular characterization of tumors is expected to increase survival rates and improve quality of life for these patients.
Tumor models based on implantation of patient biopsies in mice (PDX models) are considered to be highly relevant for preclinical therapeutic studies, particularly when tumor is implanted in the organ of origin (orthotopic). We therefore aim to 1) establish clinically representative orthotopic PDX models of metastatic endometrial cancer, and 2) use these models to assess the systemic effect of novel targeted therapies, using a maximum of 120 female NSG mice.
We hypothesize that tumor growth and metastatic dissemination in PDX mouse models will be similar to that of human endometrial cancer patients. We also anticipate that treating PDX tumors with drugs selected based on tumor biomarker expression will improve outcome in mouse models of metastatic endometrial cancer. Treatment response in PDX models is expected to be representative of the response in corrresponding human patients, and findings from preclinical treatment studies may therefore provide clinical hypotheses for treatment response in endometrial tumors with similar molecular features. Non-invasive imaging of PDX models will be used as a supplement to clincial examination for improved assessment of disease stage and therapeutic response.
Based on previous experience with orthotopic endometrial carcinoma PDX models, metastatic lesions are mostly localized to abdominal lymph nodes and parametric structures with limited burden to the animals. However, in severe cases mice may experience metastases to lungs, liver and kidneys, which can cause symptoms such as shortness of breath, jaundice and renal failure. Mice will be euthanized immediately if such conditions are suspected, thus reducing the time of distress to as short as possible. In vitro cultivation of patient cells will be tested prior to xenografting in order to eliminate non-viable samples. This will thus reduce the number of animals needed for establishment of each model (reduction). The anti-tumor effect of potential drugs will also be tested in vitro before being included in in vivo experiment, further reducing the number of animals. To limit suffering, mice will be monitored by imaging and abdominal palpation for detection of metastatic disease at an early stage. This will improve the assessment of animal welfare and identification humane endpoints (refinement).
Tumor models based on implantation of patient biopsies in mice (PDX models) are considered to be highly relevant for preclinical therapeutic studies, particularly when tumor is implanted in the organ of origin (orthotopic). We therefore aim to 1) establish clinically representative orthotopic PDX models of metastatic endometrial cancer, and 2) use these models to assess the systemic effect of novel targeted therapies, using a maximum of 120 female NSG mice.
We hypothesize that tumor growth and metastatic dissemination in PDX mouse models will be similar to that of human endometrial cancer patients. We also anticipate that treating PDX tumors with drugs selected based on tumor biomarker expression will improve outcome in mouse models of metastatic endometrial cancer. Treatment response in PDX models is expected to be representative of the response in corrresponding human patients, and findings from preclinical treatment studies may therefore provide clinical hypotheses for treatment response in endometrial tumors with similar molecular features. Non-invasive imaging of PDX models will be used as a supplement to clincial examination for improved assessment of disease stage and therapeutic response.
Based on previous experience with orthotopic endometrial carcinoma PDX models, metastatic lesions are mostly localized to abdominal lymph nodes and parametric structures with limited burden to the animals. However, in severe cases mice may experience metastases to lungs, liver and kidneys, which can cause symptoms such as shortness of breath, jaundice and renal failure. Mice will be euthanized immediately if such conditions are suspected, thus reducing the time of distress to as short as possible. In vitro cultivation of patient cells will be tested prior to xenografting in order to eliminate non-viable samples. This will thus reduce the number of animals needed for establishment of each model (reduction). The anti-tumor effect of potential drugs will also be tested in vitro before being included in in vivo experiment, further reducing the number of animals. To limit suffering, mice will be monitored by imaging and abdominal palpation for detection of metastatic disease at an early stage. This will improve the assessment of animal welfare and identification humane endpoints (refinement).