Abstract BACKGROUND Glioblastoma is an aggressive brain tumor with very limited treatment options. After surgery, remaining infiltrated tumor cells need treatment with drugs that reach these cells and that are effective. Large scale clinical trials to test promising drugs are costly and complicated due to the rareness of the disease. Development of novel drugs from the bench to clinic takes an average of 15 years, with only very few being successful. Many registered drugs have anti-cancer properties but are never clinically tested in glioblastoma. In order to create a faster and cheaper track for finding potential drugs to treat patients with glioblastoma we designed the ReDiReCCT platform. MATERIAL AND METHODS With a multidisciplinary team, including scientists, clinicians and IT specialists, a roadmap was created for selection and clinical testing of approved drugs for personalized treatment. Drugs are selected from large scale screens on patient derived glioblastoma cell cultures based on potent cytotoxic activity and with physio-chemical properties predicting BBB passage; reported effects in earlier phase 2/3 clinical trials; acceptable toxicity profiles and availability for clinical use. Selected drugs are subsequently tested in window of opportunity trials with a structured protocol for intraoperative tumor sampling to assess drug concentrations, testing standard, half or escalating doses in contrast-enhancing tumor, tumor-infiltrated brain, and blood. Drugs achieving sufficient tumoral exposure proceed to personalized drug sensitivity testing in a phase 2 trial. In parallel, tumors from each patient are analyzed by whole-genome sequencing to identify additional drugable targets. RESULTS At the start of this platform the drug selection process yielded a small set of potential drugs to be tested in our window-of -opportunity (WoO) clinical trial. The first drug tested in our WoO trial, the cholesterol inhibitor pitavastatin, reached therapeutically relevant concentrations in both enhancing tumor and tumor-infiltrated brain tissue, exceeding the levels shown to be effective in vitro. CONCLUSION We have designed a platform that enables a rational selection process for approved drugs that have clinical potential in glioblastoma treatment. These drugs undergo subsequent testing in small scale clinical trials to confirm target delivery and modification, generating a list of candidates for a personalized treatment strategy that integrates functional screening with genomic data.
Sing et al. (Wed,) studied this question.