Case study of single-cell protein activity-based drug prediction and validation for precision treatment of cholangiocarcinoma (AACR 2022)
Consensus OTar/OTr drug prediction analysis on both scRNASeq tumor cells and bulk RNA-Seq of an engrafted PDX model from resected tumor at the time of biopsy ranked Glasdegib, Plicamycin, Flavopiridol, AT9283, and Dacinostat as the top 5 drugs with best overall tumor cell coverage. Both of these drugs significantly extended survival time by Kaplan-Meier regression (p=0.001 and p=0.03, respectively). Furthermore, scRNASeq data of drug-treated PDXs showed that Dacinostat uniformly depleted all three tumor sub-populations compared to Vehicle control, whereas one of the tumor sub-clusters was resistant to Plicamycin, consistent with single-cell drug sensitivity predicted by OTr.Given the in vivo activity of these two drugs in inhibiting tumor growth, and the effectiveness of Dacinostat across observed tumor cell phenotypes, as well as the high immune infiltration of this CCA sample, these drugs may be translated into pre-clinical and clinical trials alone and in combination with checkpoint immunotherapy.