Abstract LB-127: Progastrin: a specific early cancer screening biomarker and a breakthrough innovative cancer target

Abstract

Abstract Background and aims: Because we are lacking effective screening tests, most cancers are detected in late stages, when survival rates are very low. Furthermore, despite the recent approval of targeted therapies, chemotherapy remains the cornerstone of treatment for patients suffering from these late stage cancers, such as metastatic colorectal cancer (mCRC) regardless of very low survival. Here, we show the development of the first early cancer screening test for multiple cancers using progastrin as biomarker and of the First-in-class immunotherapeutic humanized monoclonal antibody targeting progastrin and describe its therapeutic efficiency in colorectal cancer. Methods: Monoclonal antibodies of murine or humanized origin directed against progastrin were produced and selected for target specificity and affinity. Selected antibodies were either used to set up an ELISA sandwich to detect progastrin in the blood of patients with various types of cancers or validated depending on their effectiveness to regulate tumor cell growth, death and invasion in CRC cell lines mutated for BRAF or KRAS. In vitro and in vivo quantification of their efficacy was assessed, alone or concomitantly with chemotherapy, on cancer stem cells (CSCs) self-renewal capacity, tumor recurrence and Wnt signaling. Results: Increased levels of progastrin were detected in the blood of patients with various types of cancers even at early stages. Furthermore, in CRC, a boost of progastrin was detected in patients treated with chemotherapy as well as in CRC cells after chemotherapy and hypoxia-promoting conditions exposure, confirming the relevance of targeting progastrin in CRC patients under treatment. Humanized progastrin antibodies produced an intense decrease of self-renewal of CSCs both in vitro and in vivo, either alone or concomitantly with chemotherapy. Chemosensitivity was prolonged significantly and post-treatment relapse was delayed significantly as well in mice who had received multiple rounds of chemotherapy in progastrin antibody treatment conditions. Furthermore, the Wnt signaling activity in vitro was decreased, the tumor burden was alleviated, and there was an amplification in tumor differentiation in the intestine of Wnt-driven transgenic mouse neoplasia mice, all due to progastrin antibodies. Finally, 20 weeks of treatment with progastrin antibodies did not induce any alteration of organs or behavior in the treated mice. Conclusion: Taken together, the results presented here show that using progastrin as a biomarker for early cancer screening is an outstanding opportunity and that humanized progastrin antibodies alongside chemotherapy represent an extremely useful therapeutic tool allowing to target cancer stem cells while reducing the recurrence of tumors in advanced CRC. Citation Format: Alexandre Prieur, Dominique Joubert. Progastrin: a specific early cancer screening biomarker and a breakthrough innovative cancer target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-127. doi:10.1158/1538-7445.AM2017-LB-127