Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in Glioblastoma

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Many cancers have proven to be very difficult to treat due to their ability to quickly adapt and become resistant to treatment, particularly targeted therapies. A team of scientists from Cal Tech and the University of California San Diego (UCSD), led by James Heath, attempted to tackle the issue of drug resistance in glioblastoma (GBM) using single-cell phosphoproteomics.
Single-cell phosphoproteomics is able to study single or small quantities of cells, using immunoassays and antibody barcodes, in order to identify and quantify levels of specific intracellular proteins. Using this method, the researchers were able to analyze the downstream components of signaling pathways driving cancer growth/survival in order to understand how the tumor was adapting to treatment and acquiring resistance.
Specifically, Heath and his colleagues were able to show signaling changes that occurred in mouse models of GBM in response to treatment with mTOR kinase inhibitors. These alterations occurred very quickly in the course of treatment and were detected as early as 2.5 days after initiating therapy.
Moving forward, the team plans to initiate a clinical study, similar to the I-SPY-2 trial, using both genomic and proteomic data to identify new markers of drug resistance.