Abstract 4961: Novel biased PAR2 inhibitors with best-in-class properties reduce resistance to both chemotherapy and immunotherapy in oncology models
Authors: Brugat Thibaut , Bergami Francesco , Rugeri Baptiste , Janvier Aurélie , Steinberg Edith , Baron Luc , Recolet Mandy , Wirth Xavier , Semache Meriem , Mousson Antoine , Dietsch Camille , Ruet Quentin , Blanchard Orphée , Jacoberger-Foissac Célia , Cousineau Isabelle , Kadiri Maleck , Blayo Anne-Laure , Franchet Christel , Mayer Stanislas , Stagg John , Lenne Nathalie , Schann Stephan 
Published: April 2023

Abstract
A large-scale meta-analysis has recently identified Protease-activated receptor 2 (PAR2) gene expression to be significantly associated with resistance to immune checkpoint blockade (ICB) in cancer patients and preclinical models. PAR2 and its ligands (proteases) are indeed upregulated in different cancer types and are expressed by various cells in the tumor microenvironment. In cancer cells, the PAR2 receptor controls cell migration, proliferation, survival, and expression of inflammatory cytokines. In immune cells, it influences the infiltration and phenotype of macrophages and T cells. Therefore, PAR2 represents a promising therapeutic target in oncology and immuno-oncology. A novel series of potent and selective PAR2 inhibitors has been developed at Domain Therapeutics. In vitro experiments demonstrated unique properties of our PAR2 small molecule antagonists when compared to those of competitors. The antagonists inhibit pathogenic signaling pathways (i.e. Gz, G13, Gq, G14 and G15 protein activation as well as intracellular calcium) but not βarrestin2 recruitment, potentially reducing the risks of drug resistance. Furthermore, they maintain high potency and insurmountability in conditions that mimic the tumor microenvironment (high concentration of proteases and acidic pH). Finally, their pharmacokinetic properties are compatible with a once-a-day oral administration and demonstrate no signs of in vivo toxicity except at high doses (&gt;500 mg/kg). Proof-of-concept experiments showed that PAR2 antagonists prevented PAR2-mediated resistance to Gefitinib in vitro and increased the potency of anti-PD1 therapy in vivo in pre-clinical syngeneic mouse models. Immunohistochemistry analyses from cancer patient biopsies confirmed that high expression levels of PAR2 in cancer and stromal cells within the tumor microenvironment significantly associates with the patient overall survival. In conclusion, new potent and selective negative allosteric modulators of PAR2 have been developed, they demonstrate strong potency by alleviating the resistance to both chemo- and immunotherapy in cancer models. These findings confirm the high value of PAR2 as a therapeutic target and demonstrates the relevance of small molecule inhibitors targeting this receptor to treat cancer.
Citation Format: Thibaut Brugat, Francesco Bergami, Baptiste Rugeri, Aurélie Janvier, Edith Steinberg, Luc Baron, Mandy Recolet, Xavier Wirth, Meriem Semache, Antoine Mousson, Camille Dietsch, Quentin Ruet, Orphée Blanchard, Célia Jacoberger-Foissac, Isabelle Cousineau, Maleck Kadiri, Anne-Laure Blayo, Christel Franchet, Stanislas Mayer, John Stagg, Nathalie Lenne, Stephan Schann. Novel biased PAR2 inhibitors with best-in-class properties reduce resistance to both chemotherapy and immunotherapy in oncology models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4961.