Fig. 5.

Heterogeneity in patient-specific drug responses in treatment-naïve GSCs. (a) Dot plot of the distribution of the patient-specific responses (sDSS) in T1456 to all drugs with DSS ≥10 in any GSC culture displays the enrichment of proteasome inhibitor (green) clustering with increased culture specificity and the insensitivity to aurora pathway inhibitors (yellow). (b) Dot plot displaying the distribution of the drug categories clustering with the highest patient-selectivity in individual GSC cultures. Drugs are filtered by DSS ≥10 and sDSS ≥3, and drug classes are filtered by O/E ≥ 3 for the individual culture. Classes of drugs enriched in individual cultures are highlighted and display the extensive intertumoral heterogeneity in patient-specific vulnerabilities to anticancer drugs. In cultures T1459, T1506 and T1547, the top 20 selective drug responses are presented. Of the drugs with DSS ≥10, three drugs singly target HDAC, whereas two drugs (CUDC-907 and CUDC-101) have dual targets by targeting HDAC along with PI3K or EGFR/Her2, respectively. In T1547, all five drugs that singly or as a dual target inhibit HDAC were found to have the highest patient selectivity and were highlighted within the category of HDAC inhibitors. For the PLK1 inhibitors and bcl-2 inhibitors, O/E was < 3 as only 2 drugs were represented in the drug collection; however, these drugs are highlighted as they displayed unique selectivity in T1459 and T1547, respectively. (c) Dose-response curves of selected drug responses displaying the most sensitive tumor (colored line, drug response is highlighted with enhanced rim in dot plot in B) and the least sensitive tumor (black line) compared to the average response in GBM (dashed line). All drugs have (i) been tested in clinical trials of GBM (nintedanib, paclitaxel, topotecan), (ii) are currently in clinical trials of GBM (belinostat (NCT02137759), sapanisertib (NCT02142803), and selinexor (NCT01986348), clinicaltrials.gov) or (iii) represent drugs within a class that are being investigated in GBM (carfilzomib; proteasome inhibitors, idasanutlin; mdm2 inhibitors, clinicaltrials.gov). Both insensitive and highly sensitive cultures are found in response to each drug