RECURRENT GLIOBLASTOMA LONG-TERM SURVIVORS TREATED WITH CUSP9V3

Abstract CUSP9v3 is a new treatment regimen for glioblastoma. It consists of continuous daily use of 9 drugs repurposed from general medicine. Their primary non-oncology uses are given in parentheses: aprepitant (nausea), auranofin (rheumatoid arthritis), celecoxib (pain), captopril (hypertension), disulfiram (alcohol abuse), itraconazole (fungal infection), minocycline (bacterial infection), ritonavir (viral infection) and sertraline (depression). All drugs have preclinical or clinical data indicating that they can retard glioblastoma growth, as reviewed in the published background papers. In CUSP9v3 all 9 medicines are given daily with added metronomic, low-dose (20 mg/m2 BSA twice daily) temozolomide. After 3 years of daily, uninterrupted use of CUSP9v3, of an initial cohort of 10 recurrent glioblastoma patients, as of May 2021, 3 are alive, functioning well, progression-free at 44, 44, and 57 months after recurrence and CUSP9v3 started. We report now that there were no unexpected toxicities from this combination of 10 daily drugs, although all patients required dose reduction of one or more of the drugs. CUSP9v3 was reasonably well-tolerated. Ritonavir, temozolomide, captopril and itraconazole were the drugs most frequently requiring dose reduction or pausing. The most common adverse events were nausea, headache, fatigue, diarrhea and ataxia. There were no treatment-related deaths. In the 3 long-term survivors, the median neutrophil-to-lymphocyte ratio decreased from 2.5 to 1.5 during CUSP9v3 treatment. In the group of the 3 shortest-term survivors that ratio increased from 4.7 to 14.3. CUSP9v3 follows the injunction of Palmer et al. that cancer therapy can be constructed using drug combinations that are independently effective, with non-overlapping mechanisms of action, and non-overlapping resistance pathways. We interpret the data accrued over the last few decades on the ever-shifting spatial and temporal growth drives active at any given moment in glioblastoma as requiring a complex pharmacological approach like CUSP9v3.