Abstract 6126: Zebrafish patient tumor-derived xenograft models used for pre-clinical evaluation of CAN04 for lung and pancreatic cancer
Authors: Ali Zaheer , Nilsson Anna , Vildevall Malin , Schueler Julia , Liberg David , Fahlgren Anna , Jensen Lasse DE 
Published: September 2020

Lung cancer is one of the most deadly diseases accounting for 24% of all cancer deaths worldwide. One reason for this high mortality is the high interindividual heterogeneity but 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 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.

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.

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.

Citation Format: Zaheer Ali, Anna Nilsson, Malin Vildevall, Julia Schueler, David Liberg, Anna Fahlgren, Lasse DE Jensen. Zebrafish patient tumor-derived xenograft models used for pre-clinical evaluation of CAN04 for lung and pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6126.