Oncotarget

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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 _, John A. Boockvar, Ansgar Brüning, Francesco Cappello, Wen-Wei Chang, Boris Cvek, Q Ping Dou, Alfonso Duenas-Gonzalez, Thomas Efferth, Daniele Focosi, Seyed H. Ghaffari, Georg Karpel-Massler, Kirsi Ketola, Alireza Khoshnevisan, Daniel Keizman, Nicolas Magné, Christine Marosi, Kerrie McDonald, Miguel Muñoz, Ameya Paranjpe, Mohammad H. Pourgholami, Iacopo Sardi, Avishay Sella, Kalkunte S. Srivenugopal, Marco Tuccori, Weiguang Wang, Christian R. Wirtz, Marc-Eric Halatsch

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Oncotarget. 2013; 4:502-530. doi: 10.18632/oncotarget.969

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Abstract

Richard E. Kast1 , John A. Boockvar2, Ansgar Brüning3, Francesco Cappello4, Wen-Wei Chang5, Boris Cvek6, Q. Ping Dou7, Alfonso Duenas-Gonzalez8, Thomas Efferth9, Daniele Focosi10, Seyed H. Ghaffari11, Georg Karpel-Massler12, Kirsi Ketola13, Alireza Khoshnevisan14, Daniel Keizman15, Nicolas Magné16, Christine Marosi17, Kerrie McDonald18, Miguel Muñoz19, Ameya Paranjpe20, Mohammad H. Pourgholami18, Iacopo Sardi21, Avishay Sella22, Kalkunte S. Srivenugopal20, Marco Tuccori10, Weiguang Wang23, Christian R. Wirtz12, Marc-Eric Halatsch12

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.

Author Information

Richard E. Kast
Primary Contact  _

IIAIGC Headquarters 22 Church Street Burlington, VT 05401 USA

John A. Boockvar
Weill Cornell Medical College, NY, NY, USA

Ansgar Brüning
University of München, München, Germany

Francesco Cappello
University of Palermo, Palermo, Italy

Wen-Wei Chang
Chung Shan Medical University Hosptial, Taichung, Taiwan

Boris Cvek
Palacky University, Olomouc, Czech Republic

Q Ping Dou
Wayne State University, Detroit, USA

Alfonso Duenas-Gonzalez
Instituto Nacional de Cancerología, Mexico City, Mexico

Thomas Efferth
Johannes Gutenberg University, Mainz, Germany

Daniele Focosi
University of Pisa, Pisa, Italy

Seyed H. Ghaffari
Dept of Neurosurgery, Tehran University of Medical Sciences, Tehran, Iran

Georg Karpel-Massler
Dept of Neurosurgery, University of Ulm, Germany;

Kirsi Ketola
University of British Columbia, Vancouver, Canada

Alireza Khoshnevisan
Tehran University of Medical Sciences, Tehran, Iran.

Daniel Keizman
Oncology Department, Meir Medical Center, Tel Aviv University, Israel

Nicolas Magné
Institut de Cancérologie Lucien Neuwirth, Saint-Priest en Jarez, France

Christine Marosi
Neurooncology, Medical University of Vienna, Austria

Kerrie McDonald
University of New South Wales, Sydney, Australia

Miguel Muñoz
Virgen del Rocío University Hospital, Sevilla, Spain

Ameya Paranjpe
Texas Tech University Health Sciences Center, Amarillo, USA

Mohammad H. Pourgholami
University of New South Wales, Sydney, Australia

Iacopo Sardi
Neurooncology, Meyer Children's Hospital, Firenze, Italy

Avishay Sella
Assaf Harofeh Medical Center, Zerifin, Israel

Kalkunte S. Srivenugopal
Texas Tech University Health Sciences Center, Amarillo, USA

Marco Tuccori
University Hospital of Pisa, Pisa, Italy

Weiguang Wang
University of Wolverhampton, Wolverhampton, UK

Christian R. Wirtz

Marc-Eric Halatsch
Dept of Neurosurgery, University of Ulm, Ulm, Germany


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