title: Debio 0617B Inhibits Growth of STAT3-Driven Solid Tumors through Combined Inhibition of JAK, SRC, and Class III/V Receptor Tyrosine Kinases.
abstract: Tumor survival, metastases, chemoresistance, and escape from immune responses have been associated with inappropriate activation of STAT3 and/or STAT5 in various cancers, including solid tumors. Debio 0617B has been developed as a first-in-class kinase inhibitor with a unique profile targeting phospho-STAT3 (pSTAT3) and/or pSTAT5 in tumors through combined inhibition of JAK, SRC, ABL, and class III/V receptor tyrosine kinases (RTK). Debio 0617B showed dose-dependent inhibition of pSTAT3 in STAT3-activated carcinoma cell lines; Debio 0617B also showed potent antiproliferative activity in a panel of cancer cell lines and in patient-derived tumor xenografts tested in an in vitro clonogenic assay. Debio 0617B showed in vivo efficacy by inhibiting tumor growth in several mouse xenograft models. To increase in vivo efficacy and STAT3 inhibition, Debio 0617B was tested in combination with the EGFR inhibitor erlotinib in a non-small cell lung cancer xenograft model. To evaluate the impact of in vivo STAT3 blockade on metastases, Debio 0617B was tested in an orthotopic tumor model. Measurement of primary tumor weight and metastatic counts in lung tissue demonstrated therapeutic efficacy of Debio 0617B in this model. These data show potent activity of Debio 0617B on a broad spectrum of STAT3-driven solid tumors and synergistic activity in combination with EGFR inhibition. Mol Cancer Ther; 15(10); 2334-43. ©2016 AACR.
authors.affiliation: Debiopharm International S.A., Lausanne, Switzerland. mmurone@adipogen.com.
authors.forename: Maximilien
authors.initials: M
authors.lastname: Murone
authors.affiliation: Debiopharm International S.A., Lausanne, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Vaslin Chessex
authors.affiliation: Debiopharm International S.A., Lausanne, Switzerland.
authors.forename: Antoine
authors.initials: A
authors.lastname: Attinger
authors.affiliation: Aurigene Discovery Technologies, Bangalore, Karnataka, India.
authors.forename: Raghuveer
authors.initials: R
authors.lastname: Ramachandra
authors.affiliation: Aurigene Discovery Technologies, Bangalore, Karnataka, India.
authors.forename: Shankar J
authors.initials: SJ
authors.lastname: Shetty
authors.affiliation: Aurigene Discovery Technologies, Bangalore, Karnataka, India.
authors.forename: Girish
authors.initials: G
authors.lastname: Daginakatte
authors.affiliation: Aurigene Discovery Technologies, Bangalore, Karnataka, India.
authors.forename: Saumitra
authors.initials: S
authors.lastname: Sengupta
authors.affiliation: Aurigene Discovery Technologies, Bangalore, Karnataka, India.
authors.forename: Sivapriya
authors.initials: S
authors.lastname: Marappan
authors.affiliation: Aurigene Discovery Technologies, Bangalore, Karnataka, India.
authors.forename: Samiulla
authors.initials: S
authors.lastname: Dhodheri
authors.affiliation: Debiopharm International S.A., Lausanne, Switzerland.
authors.forename: Stefania
authors.initials: S
authors.lastname: Rigotti
authors.affiliation: Debiopharm International S.A., Lausanne, Switzerland.
authors.forename: Yogeshwar
authors.initials: Y
authors.lastname: Bachhav
authors.affiliation: Debiopharm International S.A., Lausanne, Switzerland.
authors.forename: Silvano
authors.initials: S
authors.lastname: Brienza
authors.affiliation: Debiopharm International S.A., Lausanne, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Traxler
authors.affiliation: Debiopharm International S.A., Lausanne, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Lang
authors.affiliation: Swiss Federal Institute of Technology, Lausanne, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Aguet
authors.affiliation: Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Zoete
authors.affiliation: Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Courtney
authors.initials: C
authors.lastname: Nicholas
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Faye M
authors.initials: FM
authors.lastname: Johnson
authors.affiliation: Aurigene Discovery Technologies, Bangalore, Karnataka, India.
authors.forename: Murali
authors.initials: M
authors.lastname: Ramachandra
authors.affiliation: Debiopharm International S.A., Lausanne, Switzerland.
authors.forename: Andres
authors.initials: A
authors.lastname: McAllister
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051379:Mice; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; D020794:Receptor Protein-Tyrosine Kinases; D053612:Janus Kinases; D019061:src-Family Kinases