High-Throughput Screening of Patient-Derived Cultures Reveals Potential for Precision Medicine in Glioblastoma

Identifying drugs for the treatment
of glioblastoma (GBM), a rapidly
fatal disease, has been challenging. Most screening efforts have been
conducted with immortalized cell lines grown with fetal bovine serum,
which have little relevance to the genomic features found in GBM patients.
Patient-derived neurosphere cultures, while being more physiologically
relevant, are difficult to screen and therefore are only used to test
a few drug candidates after initial screening efforts. Laminin has
been used to generate two-dimensional cell lines from patient tumors,
preserving the genomic signature and alleviating some screening hurdles.
We present here the first side-by-side comparison of inhibitor sensitivity
of laminin and neurosphere-grown patient-derived GBM cell lines and
show that both of these culture methods result in the same pattern
of inhibitor sensitivity. We used these screening methods to evaluate
the dependencies of seven patient-derived cell models: three grown
on laminin and four grown as neurospheres, against 56 agents in 17-point
dose–response curves in 384-well format in triplicate. This
allowed us to establish differential sensitivity of chemotherapeutic
agents across the seven patient-derived models. We found that MEK
inhibition caused patient-sample-specific growth inhibition and that
bortezomib, an FDA-approved proteasome inhibitor, was potently lethal
in all patient-derived models. Furthermore, the screening results
led us to test the combination of the Bcl-2 inhibitor ABT-263, and
the mTOR inhibitor AZD-8055, which we found to be synergistic in a
subset of patient-derived GBM models. Thus, we have identified new
candidate therapeutics and developed a high-throughput screening system
using patient-derived GBM samples.