Forsøksdyr: Humanized patient-derived xenograft model (PDX) of ovarian cancer

Godkjenningsdato 10.11.2020

Godkjenningsperiode 10.11.2020-10.11.2023

Purpose: 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, we 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. Humanized patient-derived xenografts 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 tumour from patients or established ovarian cancer cell lines.

The main focus of the current study is to develop an immunocompetent mouse model for image-guided surgery followed by immunotherapeutic treatment. New imaging contrast agents, allowing superior visualisation of tumour lesions in vivo needs to be investigated and developed to improve surgical procedures in ovarian cancer patients. In addition, immune stimulating and inhibiting therapies aim to improve treatment in ovarian cancer patients.

Anticipated adverse effects on the animals: Our planned experiments must be classified as procedures of moderate severity; The mice will undergo surgical procedures, for the orthotopic injection of tumour cells and ovariohysterectomy and tumour removal as part of treatment when disease has developed. The mice will be closely monitored during the experiments by experienced personnel. Score sheets and multi-modal anaesthetic and analgesic protocols will be used to ensure that any distress or suffering for the animals is at a minimum.

Expected scientific benefit: 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, humanized patient derived xenografts will enable us to study treatment response to novel therapeutics as for examples CAR T cell therapy and novel immune checkpoint inhibitors, and support the concept of individualized therapy in patients.

Research model. Female NOD/SCID IL2rγnull (NSG) and NOD/SCID IL2rγnull TG (CMV-IL3, CSF2, KITLG); Number 908+30

How to adhere to 3R: 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 tumour masses by specific antibody binding and PET/CT imaging 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.