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

Descripción del proyecto

Terapia peptídica contra el cáncer de ovario

El cáncer es la segunda causa de muerte en el mundo, y los tumores sólidos representan el 90 % de los casos. Esos tumores desarrollan una matriz extracelular (MEC) densa que favorece la proliferación y la resistencia del cáncer al tratamiento. Los tratamientos actuales, entre los que se incluye el uso de anticuerpos monoclonales, no suelen ser eficaces debido a la barrera estromal y a los efectos inespecíficos. En el proyecto ACT-MATRIX, financiado por el Consejo Europeo de Innovación, se pretende resolver esta limitación mediante el desarrollo de péptidos pequeños que se unan a las proteínas de la MEC, interrumpiendo así las interacciones que promueven la malignidad tumoral. El péptido TAX2 ha demostrado su capacidad para frenar la progresión tumoral, así como para mejorar la eficacia de los tratamientos con anticuerpos, en quince modelos preclínicos, entre ellos el cáncer de ovario y el cáncer de páncreas. El proyecto se centrará en el cáncer de ovario, que sigue siendo una enfermedad con importantes necesidades médicas no cubiertas y una elevada tasa de mortalidad.

Objetivo

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.