Abstract 6P
Background
The pancreatic ductal adenocarcinoma (PDAC) and advanced colorectal cancer (CRC) have a bad prognosis with delayed diagnosis that significantly impedes the use of therapeutic resection. In these situation, palliative chemotherapy has modest activity, and Immune checkpoint inhibitors or radiotherapy failed to improve survival. The proprotein convertases (PCs) are enzymes involved in the biological activation/maturation of various protein precursors crucial for the malignant phenotype of PDAC and CRC tumors, and the resistance to various anticancer treatments.
Methods
Using computer-aided virtual screening, we identified among a collection of 2082 small molecules, those with inhibitory activity against Furin, the only PCs with published crystallographic structure. 15 molecules with significant inhibitory activity. Identified molecules where then tested in vivo in syngenic murine colorectal cancer model (CT26) and on PDAC and CRC organoids generated from cells line (Capan-1, Capan-2, Panc-1 HT29, CT26) and from cancer cells from patient tumors, alone or concomitant with chemotherapy (Gemcitabine or 5-Fluorouracil), or radiotherapy. PD-1 expression was analysed in activated T cells or patients PBMCs cultured with these Furin inhibitors by flow cytometry.
Results
We identified 15 molecules with significant inhibitory activity against Furin with computered screening. Among these, 5 generated molecules ( I0, I1, I10, I13, I9), significantly reduced tumor progression and enhanced survival and sensitivity to radiotherapy in syngenic mice. Using cancer organoids in the presence of some of these molecules, the latter were more sensitive to radiotherapy and chemotherapy. Treatment of activated T cells or PBMCs with these Furin inhibitors repressed significantly PD-1 expression.
Conclusions
These findings suggest the potential efficacy of Furin inhibitors in the sensitization of PDAC and CRC to drug resistance, and the potential immune sensitization through inhibition of T cells exhaustion, that may contribute to the development of efficient therapeutic strategies and to in patients with these cancers.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Planète Végétal.
Disclosure
S. Pernot: Financial Interests, Personal, Invited Speaker: Amgen, BMS, Merck, Sanofi, Servier, Pierre Fabre. All other authors have declared no conflicts of interest.