Forsøksdyr: Immunocompetent patient derived xenograft model (PDX) for ovarian cancer


Godkjenningsdato 19.01.2018

Background and objective: In 70% of all cases, high grade serous ovarian cancer (HGSOC) is diagnosed at an advanced stage with spread into the peritoneal cavity. Despite development of surgical techniques new innovative treatment options like immunotherapeutic drugs have to be developed to circumvent innate or acquired chemo resistance.
The last years have used many efforts to establish relevant mouse models for ovarian cancer, and a bioluminescent orthotopic combined surgical/chemotherapeutic xenograft model in immunosuppressed mice has been developed. New knowledge and demands necessitate improvements. Immune-competent patient-derived xenografts (iPDX) models are suggested to be the most suitable preclinical models. These models contain both a functional human immune system as well as an orthotopically-implanted tumor from the same individual.
The main focus of the current study is to develop an immunocompetent mouse model for image-guided surgery followed by immunotherapeutic treatment.
Anticipated adverse effects on the animals: Our planned experiments must be classified as procedures of moderate severity: For the orthotopic installation of tumor cells a minor surgical procedure under general anesthesia will be used. A disease will develop, and increase abdominal girth, distress, weight-loss will be the result. After hysterectomy and tumor removal by IGS, reduced well-being may occur.
Expected scientific impact: We aim to introduce a novel clinically highly relevant humanized tumor model which serves as an optimal animal model for Image-guided surgery and immunotherapeutic treatment. Ultimately, humanised patient derived xenografts will enable us to study treatment response to novel therapeutics and support the concept of individualized therapy in patients.
Animals: Research model. Female and male NOD/SCID IL2rγnull (NSG) and NOD/SCID IL2rγnull TG (CMV-IL3, CSF2, KITLG); Number 314
How claims for compensation, reduction and improvement should be followed: The predictive values of preclinical cancer models are poor and many drugs demonstrating anti-tumor responses in vitro fail when used in clinical trials. It has been shown that PDX models originated from tissue without prior processing are superior to cell lines in modeling this complex disease. This is due to better conservation of tumor heterogeneity as well as preservation of the tumor microenvironment. In addition, our close monitoring with bioluminescence as well as detection of tumor masses by specific antibody binding will reduce the number of mice needed for the experiments. To further reduce the number of animals needed, we carefully select patient material before xenografting.
By accurate planning of invasive procedures as well as close monitoring of mice by a strictly limited number of experienced by certified personnel, we will ensure high quality of care and reduce pain, suffering, distress or lasting harm to a minimum.