Descripción del proyecto
Inestabilidad del genoma y modelos de evolución tumoral
A pesar de los progresos en el desarrollo de fármacos antineoplásicos, la mayoría de los pacientes con una enfermedad avanzada tienen un pronóstico adverso debido a la farmacorresistencia del cáncer. Estudios clínicos longitudinales han revelado que la heterogeneidad del número de copias del ADN tumoral está relacionada con la farmacorresistencia, las recidivas y la muerte en los casos de carcinoma pulmonar no microcítico (CPNM). Los modelos animales actuales de CPNM no reflejan los múltiples patrones diferentes de inestabilidad del genoma y la heterogeneidad intratumoral observada en los pacientes. El proyecto PROTEUS, financiado con fondos europeos, busca desarrollar modelos murinos de cáncer de pulmón para resumir los procesos de inestabilidad del genoma y de evasión a la respuesta inmunitaria del tumor observados en pacientes con CPNM. Esto ayudará a dilucidar los patrones evolutivos de la inestabilidad del genoma, comprender los mecanismos de evasión a la respuesta inmunitaria y probar nuevas terapias dirigidas a mejorar la estratificación de los pacientes y su tratamiento y supervivencia.
Objetivo
Despite progress in cancer drug development, the majority of patients who present with advanced, metastatic, solid tumours have incurable disease due to underlying cancer genomic diversity that provides a substrate for evolution and selection of drug resistance. The aim of this proposal is to describe, synthesise and model the micro- and macroevolutionary patterns of genomic instability underpinning the evolutionary dynamics of tumour life histories, to improve patient stratification, treatment and survival outcomes. Longitudinal clinical studies such as TRACERx are highlighting the complex processes that generate this intra-tumour heterogeneity (ITH). Genome Instability (GIN) describes aberrant changes within the genome, encompassing genome doubling (GD), numerical or structural chromosomal instability (CIN), and elevated DNA sequence mutational diversity. TRACERx has revealed that elevated DNA copy-number ITH rather than DNA sequence diversity is associated with increased risk of recurrence or death in non-small cell lung cancer (NSCLC). Why macroevolutionary CIN rather than somatic mutational diversity is associated with poor outcome remains unclear. Current animal models of NSCLC do not sufficiently model the multiple distinct patterns of GIN operating in patients. We aim to develop mouse lung cancer models that recapitulate the patterns of GIN observed in NSCLC patients. Using tumour barcode sequencing, a sensitive method of quantifying cellular fitness and individual tumour growth, we will investigate the effects of targeted-, chemo- and immuno-therapy on the newly generated GIN models. We will decipher if distinct patterns of GIN increase metastatic potential and treatment failure, and test if high mutational burden or high CIN increases the frequency of GD in cancer. Finally, we aim to investigate the effects of GIN upon immune surveillance, immune evasion, immunotherapy response, and the interactions between tumours and the tumour microenvironment.
Ámbito científico
- natural sciencesbiological sciencesgeneticsDNA
- medical and health sciencesclinical medicineoncologylung cancer
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistance
- medical and health sciencesbasic medicineimmunologyimmunotherapy
- natural sciencesbiological sciencesgeneticsgenomes
Palabras clave
Programa(s)
Régimen de financiación
ERC-ADG - Advanced GrantInstitución de acogida
NW1 1AT London
Reino Unido