Overcoming PAncreatic cancer immunotherapy resistance: developing PYRimidine receptor antagonists

The introduction of immunotherapy revolutionized cancer treatment, nevertheless, pancreatic cancer is still an omen of death with a dismal 5-year survival rate. Improvement of the current therapies for pancreatic cancer patients is thus an unmet medical need.

The research we performed for the ERC CoG ImmunoFit identified novel metabolic pathways shaping the tumor microenvironment toward immunosuppression.

Our latest publication in Nature Cancer characterized the CDA-UDP-P2Y6 axis as a major determinant of pancreatic cancer immune escape.

With this PoC grant, we want to start the valorization of our findings, generating first-in-class P2Y6 biological blockers.

Characterization of the metabolic crosstalk between cancer cells and the immune infiltrate, identified the UDP-elicited, P2Y6-dependent pathway as the most promising target to induce strong anti-tumor response and immunotherapy sensitization at minimal risk of side effects and generation of resistance.

Evaluation of the current landscape of small molecules available for P2Y6 inhibition highlighted the urgent need for an out-of-the-box approach to generate a new class of molecules suitable to target this pyrimidine receptor in vivo.

Here, we will take advantage of the specific know-how present in our host institute to generate (in collaboration with the VIB drug discovery center) VHH nanobody blockers.

The feasibility of this ambitious project is ensured by (I) the strong results supporting the scientific rationale, (II) the compelling freedom-to-operate analysis, (III) the keen evaluation of the landscape of competitors as well as (IV) the presence of an outstanding experience, within our institution, on GPCR-targeting nanobody generation.With this application, we aim to start the generation and validation of P2Y6 biological blockers and file a composition of matter patent application to foster the further clinical development of our identified lead.