Title:
Examples of translational preclinical models to mimic cancer drug resistance
Autors:
Marc Hillairet de Boisferon, Nicolas Hoffmann, Elodie Rajon, Ismahène Benzaid, Olivier Duchamp
Oncodesign Services, Dijon Cedex, France
Abstract :
Drug resistance is becoming a major obstacle when treating patients with cancer. Cancer is characterized by an uncontrolled growth of abnormal cells with permanent genome alterations, which lead to severe mutations including resistance mechanisms. Mutations can occur in different resistance pathways, such as inhibition of drug transport, DNA damage repair, drug efflux, EMT (epithelial-mesenchymal transition), drug target alteration and cell death inhibition.
Resistance mechanisms are now well studied in vitro, based on mutated cell lines for specific resistance pathways. There is however a gap in our knowledge of resistance mechanisms observed in patient tumor cells. We are challenged to discover cancer resistance treatments in patients and need predictive models of clinical situations. Animal tumor models are the best translational tools to study cancer drug resistance, especially when they closely mimic human pathologies. Such models can bridge the gap between our understanding of cancer resistance in vitro and in tumor patients. In this poster we show different pre-clinical experiments, simulating clinical translational approaches, that led to novel and unique tumor resistant models.
- Patient Derived Xenograft (PDX) models:
Using our breast cancer PDX collection we showed that after repeated treatment with a spindle poison, tumor-bearing mice started to develop resistance and continued tumor growth under drug pressure.
Following this successful approach, we initiated the development of a novel ER2-expressing PDX breast tumor model, resistant to hormone therapy by repeated Fulvestrant treatment.
Using our colon cancer PDX collection we were able to recapitulate clinical situations by correlating PDX molecular profiles and drug sensitivity. We confirmed the key role of a KRAS mutation in cetuximab resistance.
- Syngeneic model:
In this model, animals were dosed with anti-PDL1 as first line of treatment. All animals were then defined as initial responders or non-responders at the end of the dosing schedule. Following this, a new treatment protocol was initiated with a Tyrosine Kinase inhibitor to study the effect of second line drug treatment in responder and non-responder arms.
- Human model:
In this experiment, we performed a first line Avastin treatment on human colon carcinoma tumor-bearing mice. A tumor resistance to Avastin was observed. During the second line of treatment with a tyrosine kinase inhibitor, we observed an antitumor activity on Avastin resistant animals.
In each of these case studies, we developed a novel tumor-resistant mechanism model. In some tumor models, we showed the added value of treating animals with new drugs as second line treatment, after establishing resistance to the first line standard of care treatment.
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