title: A simplified interventional mapping system (SIMS) for the selection of combinations of targeted treatments in non-small cell lung cancer.
abstract: 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.
authors.affiliation: Gustave-Roussy Cancer Center, Villejuif, France.|WIN Consortium, Villejuif, France.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Lazar
authors.affiliation: Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Eitan
authors.initials: E
authors.lastname: Rubin
authors.affiliation: Leon Berard Cancer Center, Lyon, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Depil
authors.affiliation: Karolinska Institutet, Stockholm, Sweden.
authors.forename: Yudi
authors.initials: Y
authors.lastname: Pawitan
authors.affiliation: Pfizer Oncology Research, San Diego, CA, USA.|Pfizer Oncology, Pfizer Inc, New York, NY, USA.
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authors.initials: JF
authors.lastname: Martini
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: Jesus
authors.initials: J
authors.lastname: Gomez-Navarro
authors.affiliation: AstraZeneca Pharmaceuticals LP, Global Medicines Development, Gaithersburg, MD, USA.|Oncology iMED, Waltham, MA, USA.|Oncology iMED, Macclesfield, Cheshire, UK.
authors.forename: Antoine
authors.initials: A
authors.lastname: Yver
authors.affiliation: Pfizer Oncology Research, San Diego, CA, USA.|Pfizer Oncology, Pfizer Inc, New York, NY, USA.
authors.forename: Zhengyin
authors.initials: Z
authors.lastname: Kan
authors.affiliation: AstraZeneca Pharmaceuticals LP, Global Medicines Development, Gaithersburg, MD, USA.|Oncology iMED, Waltham, MA, USA.|Oncology iMED, Macclesfield, Cheshire, UK.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Dry
authors.affiliation: Sanofi, Paris, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Kehren
authors.affiliation: Institut Mutualiste Montsouris, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Validire
authors.affiliation: Vall d'Hebron Institute of Oncology Universitat Autonoma de Barcelona, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Rodon
authors.affiliation: Gustave-Roussy Cancer Center, Villejuif, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Vielh
authors.affiliation: Gustave-Roussy Cancer Center, Villejuif, France.|University Paris-Sud, Kremlin-Bicetre, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Ducreux
authors.affiliation: AstraZeneca Pharmaceuticals LP, Global Medicines Development, Gaithersburg, MD, USA.|Oncology iMED, Waltham, MA, USA.|Oncology iMED, Macclesfield, Cheshire, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Galbraith
authors.affiliation: Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
authors.forename: Manfred
authors.initials: M
authors.lastname: Lehnert
authors.affiliation: Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Amir
authors.initials: A
authors.lastname: Onn
authors.affiliation: Chaim Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Raanan
authors.initials: R
authors.lastname: Berger
authors.affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Pierotti
authors.affiliation: Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Angel
authors.initials: A
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authors.affiliation: Tata Memorial Centre, Mumbai, India.
authors.forename: C S
authors.initials: CS
authors.lastname: Pramesh
authors.affiliation: Fudan University Shanghai Cancer Center, Shanghai, China.
authors.forename: Ding-wei
authors.initials: DW
authors.lastname: Ye
authors.affiliation: Fundacao Pio XII - Barretos Cancer Hospital, Barretos, Brazil.
authors.forename: Andre L
authors.initials: AL
authors.lastname: Carvalho
authors.affiliation: Segal Cancer Centre at the Jewish General Hospital, McGill University, Montreal, QC, Canada.
authors.forename: Gerald
authors.initials: G
authors.lastname: Batist
authors.affiliation: Gustave-Roussy Cancer Center, Villejuif, France.
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authors.initials: T
authors.lastname: Le Chevalier
authors.affiliation: Gustave-Roussy Cancer Center, Villejuif, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Morice
authors.affiliation: Gustave-Roussy Cancer Center, Villejuif, France.
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authors.lastname: Besse
authors.affiliation: Gustave-Roussy Cancer Center, Villejuif, France.
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authors.affiliation: AstraZeneca Pharmaceuticals LP, Global Medicines Development, Gaithersburg, MD, USA.|Oncology iMED, Waltham, MA, USA.|Oncology iMED, Macclesfield, Cheshire, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mortlock
authors.affiliation: Karolinska Institutet, Stockholm, Sweden.
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authors.initials: J
authors.lastname: Hansson
authors.affiliation: University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania.|Ion Chiricuta Oncology Institut, Cluj-Napoca, Romania.
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authors.initials: I
authors.lastname: Berindan-Neagoe
authors.affiliation: General Electric Healthcare, Westborough, MA, USA.
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authors.lastname: Dann
authors.affiliation: Oracle Corporation, Reading, UK.
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authors.initials: J
authors.lastname: Haspel
authors.affiliation: University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania.|Ion Chiricuta Oncology Institut, Cluj-Napoca, Romania.
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authors.lastname: Irimie
authors.affiliation: Agilent Technologies, Santa Clara, CA, USA.
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authors.initials: S
authors.lastname: Laderman
authors.affiliation: Hadassah Hebrew University Medical Center, Jerusalem, Israel.
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authors.affiliation: King Hussein Cancer Center, Amman, Jordan.
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authors.initials: AS
authors.lastname: Al Omari
authors.affiliation: Blue Cross Blue Shield Association, Chicago, IL, USA.
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authors.lastname: Haywood
authors.affiliation: WIN Consortium, Villejuif, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Bresson
authors.affiliation: National Cancer Centre, Singapore.
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authors.initials: KC
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authors.affiliation: New York University Langone Medical Center, NY, USA.
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authors.lastname: Osman
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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authors.initials: JJ
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authors.affiliation: New York University Langone Medical Center, NY, USA.
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authors.affiliation: Gustave-Roussy Cancer Center, Villejuif, France.
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authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.
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authors.affiliation: Gustave-Roussy Cancer Center, Villejuif, France.
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authors.lastname: Lacroix
authors.affiliation: Gustave-Roussy Cancer Center, Villejuif, France.
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authors.lastname: Koscielny
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Karina Agda
authors.initials: KA
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authors.affiliation: Leon Berard Cancer Center, Lyon, France.
authors.forename: Jean-Yves
authors.initials: JY
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authors.affiliation: Pfizer Oncology Research, San Diego, CA, USA.|Pfizer Oncology, Pfizer Inc, New York, NY, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Buller
authors.affiliation: Gustave-Roussy Cancer Center, Villejuif, France.|University Paris-Sud, Kremlin-Bicetre, France.
authors.forename: Alexander
authors.initials: A
authors.lastname: Eggermont
authors.affiliation: American Society of Clinical Oncology (ASCO), Alexandria, VA, USA.
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authors.initials: RL
authors.lastname: Schilsky
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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authors.initials: J
authors.lastname: Mendelsohn
authors.affiliation: Gustave-Roussy Cancer Center, Villejuif, France.|University Paris-Sud, Kremlin-Bicetre, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.affiliation: Pfizer Oncology Research, San Diego, CA, USA.|Pfizer Oncology, Pfizer Inc, New York, NY, USA.
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authors.lastname: Rothenberg
authors.affiliation: Gustave-Roussy Cancer Center, Villejuif, France.|University Paris-Sud, Kremlin-Bicetre, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.affiliation: UC San Diego - Moores Cancer Center, La Jolla, CA, USA.
authors.forename: Razelle
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authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D057285:Precision Medicine / Q000379:methods*; D059467:Transcriptome
keywords: NSCLC; algorithm; pathway; targeted therapies; tri-therapy