Ddis-13. Identification of Individualized Therapy Options in Patients With Glioblastoma by High-throughput Drug Screening
Year: 2016
Type: conference-abstract
Abstract: Glioblastoma (GBM) remains rapidly fatal and identification of new treatments has proven difficult due to patient specific characteristics of the tumor. Patient-derived GBM cell cultures enriched for tumor stem cells under serum-free, growth factor-enriched conditions are able to recapitulate the human disease upon xenotransplantation. We hypothesized that patient-derived GBM cultures display patient specific drug sensitivity patterns. We cultured 12 primary GBMs and evaluated viability and cytotoxicity to 470 anticancer drugs in a 5-point dose-response curve using high-throughput screening. The drug collection consisted of both approved and investigational drugs. Screening results were verified in 5 of the screened samples to 4 effective drugs and to temozolomide, the standard of care, across assays measuring viability, cytotoxicity, sphere-forming capability and invasion. We found that inhibition of survivin by an investigational drug was lethal in all samples and effective across all assays. Furthermore, several FDA approved drugs were potent across many samples such as two proteasome inhibitors, a protein synthesis inhibitor and a RNA-/DNA-synthesis inhibitor. Several investigational drugs in clinical phases were potent in many samples, such as a Chk1/Cdk2–, a combined HDAC-/PIK3- and two HSP90 inhibitors. Interestingly, temozolomide was ineffective in all samples except one. In 9 of the screened samples a patient specific drug response was identified. We were able to reproduce the effect of potent drugs and the resistance to temozolomide in our verification set up measuring viability, cytotoxicity and sphere-forming capability. However, the effect on invasion was limited. The high-throughput screening of patient-derived GBM samples creates a drug sensitivity and resistance profile to each patient and leads to identification of possible new effective treatments. By reproducing the screening results in our verification set up we are able to reliably identify preclinical effective therapeutic options on a patient specific level with the possibility to translate preclinical data into a clinical setting.
Source: Neuro-Oncology
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2588842086