Descripción del proyecto
Información sobre las neoplasias malignas relacionadas con el tratamiento
Quienes sobreviven a un cáncer en la niñez a menudo presentan neoplasias malignas relacionadas con el tratamiento como consecuencia de su exposición a la quimioterapia o la radioterapia. Sin embargo, no se conocen bien los detalles mecanicistas sobre cómo surgen dichas neoplasias secundarias. El proyecto financiado con fondos europeos SecondCANCERinKIDS tiene por objeto investigar cómo se acumulan las mutaciones en las células madre hematopoyéticas y dan lugar a neoplasias mieloides relacionadas con el tratamiento (t-MN, por sus siglas en inglés). Para este fin, los científicos estudiarán los linajes celulares hematopoyéticos de los niños antes y después de recibir la quimioterapia para determinar si los clones ya existían previamente o si se generaron como consecuencia del tratamiento. Los resultados mostrarán en qué medida afecta la quimioterapia a la composición de la sangre y ofrecerán perspectivas nuevas sobre el origen del cáncer.
Objetivo
Therapy-related malignancies are a major cause of long-term mortality among childhood cancer survivors. However, it is unclear how exposure to chemo- and/or radiotherapy early in life induces carcinogenesis. My aim is to determine the mechanisms and rate-limiting steps underlying the genesis of second malignancies in childhood cancer survivors. For this, we will focus on studying the etiology of therapy-related myeloid malignancies (t-MNs). I have pioneered methods to characterize mutation accumulation in single stem cells and study clonal lineages in the human hematopoietic system. My lab is embedded in Europe’s largest childhood cancer center, providing the opportunity to apply our techniques to unique patient material. In Objective 1, we will dissect the life history of t-MN and study its cellular origin. Our key question is: Was the original t-MN clone already present before chemotherapy exposure, or generated as a consequence thereof? We will address this by tracking back clonal lineages in the hematopoietic tissue of patients using the mutations present in their second cancers. In Objective 2, we will study the mutational consequences of chemotherapy in normal hematopoietic cells of children before and after they received treatment. Our key question is: Is enhanced mutagenesis rate limiting for t-MN development? To address this, we will perform in-depth mutational analyses and in vitro validations. In Objective 3, we will determine phenotypic effects of chemotherapy on population dynamics of blood. Our key question is: how does chemotherapy affect selection dynamics and clonal composition of blood? To address this, we will integrate clonal histories and lineage contributions using somatically acquired mutations. Our unique methodology and anticipated novel insights will not contribute to improved survival of children with cancer, but also to increased fundamental knowledge on the origin of cancer.
Ámbito científico
Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
3584CS Utrecht
Países Bajos