Well into the era of cancer genomics, Glioblastoma (GBM) remains one of the most treatment-resistant tumors. A defining challenge lies in GBM’s extreme heterogeneity; many seemingly actionable alterations occur later in tumor evolution and exist only in subsets of cells, limiting pan-tumor efficacy. Interestingly, some of the best candidates for early clonal events are not focal in nature but rather occur as large-scale aneuploidies in which chromosome arms are gained or lost. Among the most common aneuploidies in GBM are chromosome 7 gains and losses of 9p and 10, which collectively affect hundreds of genes. As these events often occur early in tumor development, virtually all tumor cells are affected, opening the potential for more durable therapeutic opportunities. Despite their prevalence, the biological consequences and therapeutic vulnerabilities created by these aneuploidies remain poorly understood.
This Endeavor award brings together complementary expertise in computational genetics, combinatorial genetic screening, and advanced GBM models to systematically dissect the role of these chromosomal alterations. By integrating state-of-the-art in vitro and in vivo approaches, the project will identify both oncogenes and tumor suppressors that cooperate within these aneuploid regions, as well as the genetic interactions that drive tumor fitness. A particular emphasis will be placed on uncovering dependencies that arise not only from canonical drivers but also from passenger alterations, creating opportunities for synthetic lethal therapeutic strategies.
A critical strength of the project is its use of powerful new experimental models. Patient-derived cell lines and next-generation in vivo CRISPR systems will be leveraged to better capture the complexity of tumor–microenvironment interactions, while high-throughput combinatorial screens will make it possible to disentangle the contributions of dozens of genes altered by large chromosomal events. These efforts will be complemented by analytic frameworks that extract insights into tumor evolution directly from patient datasets, ensuring that findings remain tightly connected to human disease.
By systematically mapping the functional consequences of aneuploidy, the project seeks to open new avenues for precision oncology in GBM, addressing a critical unmet need in a disease where other strategies have repeatedly fallen short. Harnessing the insights gained from this project will have the potential to transform the treatment of this recalcitrant tumor.