RESUMEN
SUMMARY: Here, we define a future of cancer team science adopting "radical collaboration"-in which six "Hallmarks of Cancer Collaboration" are utilized to propel cancer teams to reach new levels of productivity and impact in the modern era. This commentary establishes a playbook for cancer team science that can be readily adopted by others.
Asunto(s)
Conducta Cooperativa , Neoplasias , Humanos , Investigación Interdisciplinaria , Neoplasias/terapiaRESUMEN
Reducing disparities is vital for equitable access to precision treatments in cancer. Socioenvironmental factors are a major driver of disparities, but differences in genetic variation likely also contribute. The impact of genetic ancestry on prioritization of cancer targets in drug discovery pipelines has not been systematically explored due to the absence of pre-clinical data at the appropriate scale. Here, we analyze data from 611 genome-scale CRISPR/Cas9 viability experiments in human cell line models to identify ancestry-associated genetic dependencies essential for cell survival. Surprisingly, we find that most putative associations between ancestry and dependency arise from artifacts related to germline variants. Our analysis suggests that for 1.2-2.5% of guides, germline variants in sgRNA targeting sequences reduce cutting by the CRISPR/Cas9 nuclease, disproportionately affecting cell models derived from individuals of recent African descent. We propose three approaches to mitigate this experimental bias, enabling the scientific community to address these disparities.
Asunto(s)
Sistemas CRISPR-Cas , Mutación de Línea Germinal , Humanos , Edición Génica/métodos , ARN Guía de Sistemas CRISPR-Cas/genética , Células Germinativas/metabolismo , Variación Genética , Neoplasias/genética , Reacciones Falso Negativas , Genoma Humano , Línea Celular Tumoral , Línea CelularRESUMEN
Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies remains challenging in part due to the lack of faithful preclinical in vitro models. Here we establish twelve patient-derived WT cell lines and demonstrate that these models faithfully recapitulate WT biology using genomic and transcriptomic techniques. We then perform loss-of-function screens to identify the nuclear export gene, XPO1, as a vulnerability. We find that the FDA approved XPO1 inhibitor, KPT-330, suppresses TRIP13 expression, which is required for survival. We further identify synergy between KPT-330 and doxorubicin, a chemotherapy used in high-risk FHWT. Taken together, we identify XPO1 inhibition with KPT-330 as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.