Metabolic checkpoints

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Hijacking metabolic pathways

One particularity of tumors is their capacity to hijack cellular metabolic pathways to bypass immunosurveillance via the development of a strategy enabling the tumor to spread, to proliferate, or to protect itself from an immune or therapeutic attack. This can be achieved through the production of immunosuppressive metabolic byproducts, or metabolic checkpoints, such as adenosine, kynurenine, PGE2, norepinephrine, epinephrine, lipids, lactate or protons. Despite their implication in immunosuppression, there are currently no therapies for cancer indications addressing these metabolic checkpoints.


Metabolic checkpoints and GPCRs

On a therapeutic strategy point of view, two approaches can be considered to interfere with metabolic checkpoints; the development of new drugs either aiming at inhibiting the synthesis of these metabolic byproducts, or aiming at blocking their immunosuppressive activities. Interestingly, many of these metabolic checkpoints mediate their activities through the activation of GPCRs, and the second approach based on inhibition of immunosuppressive activities therefore applies perfectly to the development of antagonists or negative allosteric modulators based on small molecule entities. This is the strategy for the A2AR-A2BR dual antagonist and the EP4R-antagonist programs Domain Therapeutics has developed, but also for novel programs based on both small molecule entity and antibody, currently under development in the company.


Metabolic checkpoints and drug development

A strategic aspect of therapeutic programs targeting metabolic checkpoints is the fact that the enzymes & transporters responsible for the production and release of metabolic checkpoints in the tumor microenvironment can be used as specific biomarkers. Those markers will help the identification and the selection of cancer types and cancer sub-population engaging the most the respective metabolic pathway and thus being more likely to response to the immunotherapy targeting a specific metabolic checkpoints. The metabolic checkpoint or its metabolite dosage can also be used for the same purpose of selecting the right population in the clinic. This strategy consisting in investing many efforts in biomarker development is key for R&D programs at Domain Therapeutics.