Targeting the undruggable: Leveraging neomorphic DNA-binding preferences of chimeric fusion oncogenes to promote cancer suicide

Descripción del proyecto

Oncogenes para el suicidio de las células cancerosas

La aparición y evolución del cáncer suelen estar impulsadas por factores de transcripción oncogénicos (OTF, por sus siglas en inglés) que alteran el proceso celular normal y provocan una división celular descontrolada. Los OTF se forman por anomalías genéticas o translocaciones cromosómicas y han servido de diana para intervenciones terapéuticas. Sin embargo, las características estructurales y funcionales particulares de determinados OTF los hacen inutilizables. El equipo del proyecto Cancer-Harakiri, financiado por el Consejo Europeo de Investigación, pretende abordar este problema aprovechando las preferencias particulares de unión al ADN de los OTF para una estrategia terapéutica novedosa. La idea es delinear el paisaje regulador de los OTF e identificar los genes que regulan su actividad. El objetivo final es inducir el suicidio de las células cancerosas.

Objetivo

Many aggressive cancers, such as pediatric high-risk Ewing sarcoma and alveolar rhabdomyosarcoma, are fueled by and addicted to chimeric oncogenic transcription factors (OTFs). So far, all attempts to suppress these potent OTFs largely failed, wherefore they are classified as undruggable.
This proposal challenges this dogma with a novel strategy to leverage, rather than to suppress, the exquisite neomorphic DNA-binding preferences of OTFs to express therapeutic genes specifically in cancer cells. In pursuing three ambitious aims, this project goes far beyond an original proof-of-concept study in which we drove pediatric cancer cells in preclinical models into suicide (CANCER-HARAKIRI) via viral transfer of therapeutic genes induced by the specific interaction of an OTF with its neomorphic DNA-binding motif:
In Aim 1, we will genetically engineer and functionally test a conceptionally advanced viral vector in vivo with optimized general design, oncotropism, and therapeutic payload focusing on immuno-oncological aspects.
In Aim 2, we will comprehensively map the regulome of OTFs using novel reporter cell lines, single-cell sequencing, RNAi-screens, and CRISPR interference to identify and validate OTF-inhibiting genes that can be co-targeted in our vector to prevent escape variants with low OTF-activity.
In Aim 3, we will integrate insights from Aims 1&2 into our new vector design, translate our therapeutic approach from our main model entity, Ewing sarcoma, to other OTF-driven cancers, and set the stage for GMP-compliant virus production and initiation of a clinical trial.
This integrative approach combines expertise and technology across disciplines with original experimental tools to afford a comprehensive understanding of the OTF-regulome, and to rationally design and leap ahead an innovative therapeutic concept, which has the potential to revolutionize the therapy of metastatic OTF-driven cancers. Thus, we will exploit the undruggable to promote CANCER-HARAKIRI.