DDIS-05. PATIENT DERIVED NEUROSPHERE CULTURES IDENTIFY NOVEL CHEMOVULNERABILITIES IN GLIOBLASTOMA

摘要

3-dimensional (3D) cell culture systems are increasingly used in biomedical research due to their recapitulation of tumor architecture, including pertinent nutrient and oxygen gradients, and a requisite drug penetration through multiple cell layers. Deployment of patient derived models of cancer (PDMC) propagated in defined media (serum-free) heightens clinical relevance of drug activity over that of long-term established cell lines, with an expectation of greater preclinical prediction of efficacy in patients. Indeed 3D tumor models retain the genomic heterogeneity and “stem-like” properties of the original tumors. Here we report results from screening 3D neurosphere cultures of 24 different glioblastoma (GBM) PDMC with focused, clinically-relevant, drug collections. In addition to uncovering patient-specific agents (Precision Medicine), the approach uncovers sub-stratification of GBM into novel chemosensitive groups. Specifically, cases dichotomize into instances of sensitivity to targeted agents such as proteasome inhibitors or those of growth factor signaling (e.g. TGFβ pathway modulators), although many novel targets are also identified. We further employ genomic and gene expression analyses to characterize said groups with a view to illustrating these chemovulnerabilities to detect the relevant signaling pathways’ therapeutic intervention points. In sum, using clinically-relevant PDMCs and 3D culture systems, we can identify drugs and novel targets relevant to individual patients. Once further validated, genomic characterization of new patient cultures could be used to predict sensitivity to certain perturbagens, making a case for evidence-based precision medicine. As current GBM treatment options are particularly limited, this approach may help provide insights for optimal use of available therapeutics.