Novel peptide-based therapeutics for reprogramming the tumour stroma extracellular matrix using molecular modelling and computational engineering

Description du projet

Une thérapie à base de peptides contre le cancer de l’ovaire

Le cancer est la deuxième cause de décès dans le monde, les tumeurs solides comptant pour 90 % des cas. Ces tumeurs développent une matrice extracellulaire (MEC) dense qui favorise la croissance du cancer et la résistance aux traitements. Les thérapies actuelles, dont les anticorps monoclonaux, échouent souvent en raison de la barrière stromale et des effets hors cible. Le projet ACT-MATRIX, financé par le CEI, entend relever ce défi en développant de petits peptides qui se lient aux protéines de la MEC, perturbant ainsi les interactions qui favorisent l’agressivité des tumeurs. Dans 15 modèles précliniques, dont des cancers de l’ovaire et du pancréas, le peptide TAX2 a démontré qu’il pouvait ralentir la progression de la tumeur et améliorer l’efficacité des thérapies à base d’anticorps. Le projet sera principalement axé sur le cancer de l’ovaire, qui reste une maladie contre laquelle la médecine est fort mal armée et dont le taux de mortalité est extrêmement élevé.

Objectif

Cancer is the second biggest cause of death worldwide. 90% of cancers are solid tumours, where tumour stromal cells secrete a dense mass of proteins called the extracellular matrix (ECM), part of a protective tumour microenvironment that promotes cancer proliferation, invasiveness, and resistance to chemotherapy and biologics. Several therapies now available or being developed rely on monoclonal antibodies aimed at tumour-expressed antigens, or activation of immune cells. Many such promising immunotherapeutic approaches fail because of this stromal barrier, and/or because of toxicity due to off-target effects. Targeting proteins and pathways in the tumour microenvironment is now considered by oncology experts and pharmaceutical concerns to be critical to the success of beating solid tumours, but no therapies have yet emerged to address this €200+B market. Our platform uses novel molecular computational simulation models to generate small peptides that bind to highly specific sites on ECM proteins and block interactions known to promote tumour aggressiveness. The first of these, TAX2, selectively targets a clinically relevant interaction between the ECM signalling protein Thrombospondin-1 and its receptors, to regulate tumour proliferation, vascularisation, and immune cell (T-cell) infiltration of the tumour. TAX2 shows extremely promising results in 15 preclinical models, including ovarian, pancreatic, colorectal, and melanoma cancers, where it inhibits tumour progression and metastasis. TAX2 also substantially improves the efficacy of antibody therapies when combined in these models. Our current focus is on ovarian cancer, a cancer with high unmet need, and very high mortality rate. EIC support will enable large-scale manufacture, regulatory steps, and first-in-human, multi-indication clinical trials (Ph I and Ph IIa) in preparation for outlicensing of TAX2 to a pharmaceutical partner who would take the therapy through more advanced clinical trial stages.