Vijay Padul, PhD

Glioblastoma is the most common and most aggressive primary malignant brain tumor in adults. Despite therapeutic interventions, the glioblastoma prognosis remains very poor as most patients die within 12 months after diagnosis. Current standard treatment for glioblastoma (GBM) is neurologically safe maximal surgical resection of the tumor, irradiation and chemotherapy with temozolomide. This treatment results in progression-free survival of 6.7 months, overall survival of 16.0 months, and 2-year overall survival of 30.7%. This poor survival is due to the diffuse nature of the tumor where cancer cells migrate and start growing in the surrounding normal part of the brain. This leads to recurrence of the tumor which usually takes place within a year after initial treatment. The recurrent cancer cells evolve and develop resistance to the drug therapy and form a heterogeneous tumor which no longer responds to drug therapy. Due to this glioblastoma is one of the most challenging malignancies to treat in all of oncology. Currently, there is no commonly accepted standard of care for recurrent glioblastoma, and no therapeutic regimen has proven to be safe and effective for this fatal tumor. As the dismal prognosis of glioblastoma may be related to the ability of glioblastoma cells to develop mechanisms of treatment resistance, one way to tackle this treatment resistance may be to use multiple drugs simultaneously, which may target multiple pathways in glioblastoma cells, which will leave minimum scope for the malignant cells to develop drug resistance. In 2013, Halatsch et al., proposed a new concept to treat patients with recurrent glioblastoma called Coordinated Undermining of Survival Paths (CUSP). The CUSP therapeutic approach aims to block growth-driving signaling pathways active in glioblastoma by using multiple drugs. The group adopted drug repurposing strategy. They identified nine already-marketed non-oncological drugs with evidenced efficacy to inhibit one or more of the identified growth and cell survival pathways in glioblastoma cells. These 9 drugs were proposed to be used with low-dose, continuous temozolomide. They considered pharmacology, drug interaction, and safety considerations for this combination. This 9 drug treatment regimen was called as CUSP9v3 which means ‘Coordinated Undermining of Survival Paths combining 9 repurposed non-oncological drugs with metronomic temozolomide—version 3’. The research article describes the phase Ib/IIa trial of the CUSP9v3 protocol to assess the safety of the treatment regimen in recurrent glioblastoma patients. This phase Ib/IIa trial included ten adults with histologically confirmed glioblastoma with recurrent or progressive tumor. The CUSP9v3 treatment consisted of nine drugs which are aprepitant, auranofin, celecoxib, captopril, disulfiram, itraconazole, minocycline, ritonavir, and sertraline. These drugs were added to metronomic low-dose temozolomide. Treatment was continued until toxicity or progression. Primary endpoint was dose-limiting toxicity defined as either any unmanageable grade 3–4 toxicity or inability to receive at least 7 of the 10 drugs at ≥ 50% of the per-protocol doses at the end of the second treatment cycle. Out of ten patients, 9 evaluable patients met the primary endpoint while one patient was not evaluable for the primary endpoint (safety). The treatment regimen was concluded to be well-tolerated. The most frequent dose modification or pausing was required for the drugs Ritonavir, temozolomide, captopril, and itraconazole. The most common adverse events to occur were nausea, headache, fatigue, diarrhea, and ataxia. Progression-free survival at 12 months was 50%. This phase Ib/IIa trial concluded that CUSP9v3 can be safely administered in patients with recurrent GBM under careful monitoring. The group is planning a randomized phase II trial to assess the efficacy of the CUSP9v3 regimen in glioblastoma. This research article presents the first step in establishing that an extensive multi-drug regimen is tolerable in glioblastoma patients.