Zebrafish PDX model as screening tool - AACR 2020

16 June 2020

This is the third and last abstract that will be presented as poster at AACR in June. If you are interested in learning more or how zebrafish models could help you in your development process, do not hesitate to contact us at info@bioreperia.com or in the contact form below.

Title: Zebrafish patient tumor-derived xenograft models used for pre-clinical evaluation of CAN04 for lung and pancreatic cancer

Authors: Zaheer Ali, Anna Nilsson, Malin Vildevall, Julia Schueler, David Liberg, Anna Fahlgren, Lasse D. Jensen

This study was made as a collaboration between BioReperia AB, Cantargia AB and Charles River Laboratories.

Introduction

Lung and pancreatic cancer are among the deadliest malignant diseases accounting for 24% of all cancer deaths or 80% mortality within 1-year respectively. One reason for this high mortality is extensive patient heterogeneity and generally poor efficacy of current treatments, leading to an urgent need for new and more effective drugs.
Understanding the individual variability in the efficacy of new treatment candidates, delineating whether they should be combined with existing chemotherapeutics, and to what extent they affect metastatic dissemination of the tumor cells, are key preclinical indicators needed to increase the chance of success in clinical trials. Developing such data, however, requires animal models that recapitulate individual differences of different lung and pancreatic cancer patients, include insights into metastatic activity and allow analysis of a large amounts of treatment combinations for each patient model.

As such, an in vivo screening system which has higher throughput than mouse models and at the same time allows analysis of metastatic activity would be very valuable in mimicking human disease.

Results

Here we conducted zebrafish patient tumor derived xenograft (PDX)-studies based on cisplatin sensitive and -resistant lung cancer PDX material, to test the efficacy of a a novel antibody, CAN04, under development for this indication. CAN04 targets Interleukin-1 Accessory Protein (IL1RAP) and has shown synergistic effects with cisplatin in murine models of cancer. CAN04 is currently in phase II development in combination with chemotherapy in lung cancer and pancreatic cancer. CAN04 was given either alone or with cisplatin at three different concentrations, and the effects on primary tumor growth and metastasis three days after tumor implantation was evaluated. We show that CAN04 was able to synergize with cisplatin in causing almost complete (85%-98%) tumor regression even of cisplatin-resistant tumors, compared to non-treated controls. The effects were concentration- and model-dependent. Interestingly, in the cisplatin-resistant model, the antibody and cisplatin co-treatment led to robust inhibition of metastatic dissemination, which was not seen in either group alone. This substantiates the beneficial therapeutic efficacy of combining CAN04 to cisplatin treatment in lung cancer.

* Since the abstract was submitted, data on pancreatic cancer has been generated, and will be presented in more detail on the poster. All posters will be avaliable on our home page after the conference.

Conclusion

In conclusion, zebrafish-PDX (ZTX) models are powerful tools for evaluating individual differences in drug sensitivity on both primary tumor growth and metastasis and are suitable for screening various drug concentrations and/or combinations in multiple models with results being generated within one or a few weeks. We further conclude that CAN04 is inducing cisplatin sensitivity and synergize with cisplatin to inhibit metastasis, at least in some cisplatin resistant lung cancers.

The poster will be presented in session PO.TB01.06- Model organisms for Cancer Research June 22nd and have the code 6126/10

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