A conceptually new treatment approach for relapsed glioblastoma: Coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care

// Richard E. Kast 1 , John A. Boockvar 2 , Ansgar Brüning 3 , Francesco Cappello 4 , Wen-Wei Chang 5 , Boris Cvek 6 , Q. Ping Dou 7 , Alfonso Duenas-Gonzalez 8 , Thomas Efferth 9 , Daniele Focosi 10 , Seyed H. Ghaffari 11 , Georg Karpel-Massler 12 , Kirsi Ketola 13 , Alireza Khoshnevisan 14 , Daniel Keizman 15 , Nicolas Magné 16 , Christine Marosi 17 , Kerrie McDonald 18 , Miguel Muñoz 19 , Ameya Paranjpe 20 , Mohammad H. Pourgholami 18 , Iacopo Sardi 21 , Avishay Sella 22 , Kalkunte S. Srivenugopal 20 , Marco Tuccori 10 , Weiguang Wang 23 , Christian R. Wirtz 12 , Marc-Eric Halatsch 12 1 IIAIGC Headquarters, Dean of Studies, Burlington, VT, USA 2 Weill Cornell Medical College, NY, USA 3 University of München, München, Germany 4 University of Palermo, Palermo, Italy 5 Chung Shan Medical University Hospital, Taichung, Taiwan 6 Palacky University, Olomouc, Czech Republic 7 Wayne State University, Detroit, USA 8 Instituto de Investigaciones Biomedicas UNAM, Instituto Nacional de Cancerología, Mexico City, Mexico 9 Johannes Gutenberg University, Mainz, Germany 10 University of Pisa, Pisa, Italy 11 Tehran University of Medical Sciences, Tehran, Iran 12 University of Ulm, Ulm, Germany 13 University of British Columbia, Vancouver, Canada 14 Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran 15 Oncology Department, Meir Medical Center, Tel Aviv University, Israel 16 Institut de Cancérologie Lucien Neuwirth, Saint-Priest en Jarez, France 17 Medical University of Vienna, Wein, Austria 18 University of New South Wales, Sydney, Australia 19 Virgen del Rocío University Hospital, Sevilla, Spain 20 Texas Tech University Health Sciences Center, Amarillo, USA 21 Meyer Children’s Hospital, Firenze, Italy 22 Assaf Harofeh Medical Center, Zerifin, Israel 23 University of Wolverhampton, Wolverhampton, UK Correspondence: Richard E. Kast , email: // Marc-Eric Halatsch , email: // Keywords : angiotensin, aprepitant, artesunate, auranofin, captopril, cytokines, disulfiram, glioblastoma, ketoconazole, nelfinavir, neurokinin, sertraline, temozolomide Received : April 7, 2013 Accepted : April 11, 2013 Published : April 13, 2013 Abstract To improve prognosis in recurrent glioblastoma we developed a treatment protocol based on a combination of drugs not traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications. Focus was on adding drugs which met these criteria: a) were pharmacologically well characterized, b) had low likelihood of adding to patient side effect burden, c) had evidence for interfering with a recognized, well-characterized growth promoting element of glioblastoma, and d) were coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological features of glioblastoma growth. We found nine drugs meeting these criteria and propose adding them to continuous low dose temozolomide, a currently accepted treatment for relapsed glioblastoma, in patients with recurrent disease after primary treatment with the Stupp Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, CUSP9, then are aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, sertraline, to be added to continuous low dose temozolomide. We discuss each drug in turn and the specific rationale for use- how each drug is expected to retard glioblastoma growth and undermine glioblastoma’s compensatory mechanisms engaged during temozolomide treatment. The risks of pharmacological interactions and why we believe this drug mix will increase both quality of life and overall survival are reviewed.