Research Papers:

A simplified interventional mapping system (SIMS) for the selection of combinations of targeted treatments in non-small cell lung cancer

Vladimir Lazar _, Eitan Rubin, Stephane Depil, Yudi Pawitan, Jean-François Martini, Jesus Gomez-Navarro, Antoine Yver, Zhengyin Kan, Jonathan R. Dry, Jeanne Kehren, Pierre Validire, Jordi Rodon, Philippe Vielh, Michel Ducreux, Susan Galbraith, Manfred Lehnert, Amir Onn, Raanan Berger, Marco A. Pierotti, Angel Porgador, CS Pramesh, Ding-wei Ye, Andre L. Carvalho, Gerald Batist, Thierry Le Chevalier, Philippe Morice, Benjamin Besse, Gilles Vassal, Andrew Mortlock, Johan Hansson, Ioana Berindan-Neagoe, Robert Dann, Joel Haspel, Alexandru Irimie A, Steve Laderman, Hovav Nechushtan, Amal S. Al Omari, Trent Haywood, Catherine Bresson, Khee Chee Soo, Gary Palmer, Ludovic Lacroix, Serge Koscielny, Karina Agda Eterovic, Jean-Yves Blay, Richard Buller, Alexander Eggermont, Richard L. Schilsky, John Mendelsohn, Jean-Charles Soria, Mace Rothenberg, Jean-Yves Scoazec, Waun Ki Hong and Razelle Kurzrock

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Oncotarget. 2015; 6:14139-14152. https://doi.org/10.18632/oncotarget.3741

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Vladimir Lazar1,2, Eitan Rubin3,*, Stephane Depil4,*, Yudi Pawitan5,*, Jean-François Martini6,7, Jesus Gomez-Navarro8, Antoine Yver9,10,11, Zhengyin Kan6,7, Jonathan R. Dry9,10,11, Jeanne Kehren12, Pierre Validire13, Jordi Rodon14, Philippe Vielh1, Michel Ducreux1,15, Susan Galbraith9,10,11, Manfred Lehnert8, Amir Onn16, Raanan Berger16, Marco A. Pierotti17, Angel Porgador3, CS Pramesh18, Ding-wei Ye19, Andre L. Carvalho20, Gerald Batist21, Thierry Le Chevalier1, Philippe Morice1, Benjamin Besse1, Gilles Vassal1, Andrew Mortlock9,10,11, Johan Hansson5, Ioana Berindan-Neagoe22,23, Robert Dann24, Joel Haspel25, Alexandru Irimie22,23, Steve Laderman26, Hovav Nechushtan27, Amal S. Al Omari28, Trent Haywood29, Catherine Bresson2, Khee Chee Soo30, Iman Osman31, Hilario Mata32, Jack J. Lee32, Komal Jhaveri31, Guillaume Meurice1, Gary Palmer33, Ludovic Lacroix1, Serge Koscielny1, Karina Agda Eterovic32, Jean-Yves Blay4, Richard Buller6,7, Alexander Eggermont1,15, Richard L. Schilsky34, John Mendelsohn32, Jean-Charles Soria1,15, Mace Rothenberg6,7, Jean-Yves Scoazec1,15,*, Waun Ki Hong32,* and Razelle Kurzrock35,*

1 Gustave-Roussy Cancer Center, Villejuif, France

2. WIN Consortium, Villejuif, France

3 Ben-Gurion University of the Negev, Beer-Sheva, Israel

4 Leon Berard Cancer Center, Lyon, France

5 Karolinska Institutet, Stockholm, Sweden

6 Pfizer Oncology Research, San Diego, CA

7 Pfizer Oncology, Pfizer Inc, New York, NY, USA

8 Takeda Pharmaceuticals International Co., Cambridge, MA, USA

9 AstraZeneca Pharmaceuticals LP, Global Medicines Development, Gaithersburg MD, USA

10 Oncology iMED, Waltham, MA, USA

11 Oncology iMED, Macclesfield, Cheshire UK

12 Sanofi, Paris, France

13 Institut Mutualiste Montsouris, Paris, France

14 Vall d’Hebron Institute of Oncology Universitat Autonoma de Barcelona, Barcelona, Spain

15 University Paris-Sud, Kremlin-Bicetre, France

16 Chaim Sheba Medical Center, Tel-Hashomer, Israel

17 Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

18 Tata Memorial Centre, Mumbai, India

19 Fudan University Shanghai Cancer Center, Shanghai, China

20 Fundacao Pio XII – Barretos Cancer Hospital, Barretos, Brazil

21 Segal Cancer Centre at the Jewish General Hospital, McGill University, Montreal, QC, Canada

22 University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania

23 Ion Chiricuta Oncology Institut, Cluj-Napoca, Romania

24 General Electric Healthcare, Westborough, MA, USA

25 Oracle Corporation, Reading, UK

26 Agilent Technologies, Santa Clara, CA, USA

27 Hadassah Hebrew University Medical Center, Jerusalem, Israel

28 King Hussein Cancer Center, Amman, Jordan

29 Blue Cross Blue Shield Association, Chicago, IL, USA

30 National Cancer Centre, Singapore

31 New York University Langone Medical Center, NY, USA

32 The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

33 Foundation Medicine Inc., Cambridge, MA, USA

34 American Society of Clinical Oncology (ASCO), Alexandria, VA, USA

35 UC San Diego - Moores Cancer Center, La Jolla, CA, USA

* These authors have contributed equally to this work


Vladimir Lazar, email:

Keywords: Tri-therapy, NSCLC, targeted therapies, algorithm, pathway

Received: January 19, 2015 Accepted: March 02, 2015 Published: April 03, 2015


Non-small cell lung cancer (NSCLC) is a leading cause of death worldwide. Targeted monotherapies produce high regression rates, albeit for limited patient subgroups, who inevitably succumb. We present a novel strategy for identifying customized combinations of triplets of targeted agents, utilizing a simplified interventional mapping system (SIMS) that merges knowledge about existent drugs and their impact on the hallmarks of cancer. Based on interrogation of matched lung tumor and normal tissue using targeted genomic sequencing, copy number variation, transcriptomics, and miRNA expression, the activation status of 24 interventional nodes was elucidated. An algorithm was developed to create a scoring system that enables ranking of the activated interventional nodes for each patient. Based on the trends of co-activation at interventional points, combinations of drug triplets were defined in order to overcome resistance. This methodology will inform a prospective trial to be conducted by the WIN consortium, aiming to significantly impact survival in metastatic NSCLC and other malignancies.

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