EP4 receptor antagonist, tackling immunosuppression in the tumor microenvironment

Amongst the different immunosuppressive pathways triggered by cancer to progress, releasing prostaglandin E2 ( PGE2 ) in the tumor microenvironment is one of the multiple strategy used by  several solid tumors such as breast, colon or lung cancers to bypass immune system. Prostaglandin E2 activates G-protein coupled receptors (GPCRs) located on immune cells to induce immunosuppression. This mechanism is mainly driven by the EP4 receptor, a GPCR, and has led Domain Therapeutics to discover of new chemical entity able to inhibit the prostaglandin E2 – EP4 receptor interaction. Thus, antagonizing the prostaglandin E2 – EP4 receptor axis acts like an immune system booster in tumor expressing such an immunosuppression strategy.

The prostaglandin E2 immunosuppressive pathways

Multiple genes involved in the prostaglandin E2 pathway are dysregulated in solid tumors, underlying the immunosuppression mechanism mediated by this metabolite. This includes COX-2 and 15-PGDH, respectively in charge of the biosynthesis and the degradation of prostaglandin E2. Indeed, aberrant COX-2 gene expression has been reported in many cancers of epithelial origin and elevated levels of this inducible enzyme are often associated with poor prognosis. On the opposite, downregulation of the 15-PGDH gene, considered as a tumor suppressor gene, has also been reported in many tumors. Such enzyme dysregulations will result in prostaglandin E2 accumulation in the tumor microenvironment that will sustainably activate the EP4 receptor located on immune cells leading to an immunosuppression status.

DT-9081, Domain’s EP4 receptor clinical candidate

Thanks to its expertise in GPCR drug discovery, Domain Therapeutics discovered series of small molecule EP4 receptor antagonist. Among them, the candidate DT-9081 has been selected and is progressing towards the clinic. By blocking prostaglandin E2 activation of the EP4 receptor, DT-9081 acts as an immune system booster able to synergize with standard immune checkpoint inhibitors.

Preclinical package and development plan of Domain Therapeutics’ candidate DT-9081

DT-9081 has been fully characterized in preclinical studies including multiple syngeneic mouse models, demonstrating an improvement of responses to anti-PD-1 or anti-CTLA-4 treatments in combination. In human blood studies, DT-9081 normalized activity on pro- and anti-inflammatory cytokine release. In addition, Domain Therapeutics has translated a complete and robust biomarker strategy monitoring target engagement and efficacy to support clinical development and cancer type prioritization. DT-9081 entered phase I in late 2022.