title: HER2-Targeted Polyinosine/Polycytosine Therapy Inhibits Tumor Growth and Modulates the Tumor Immune Microenvironment.
abstract: The development of targeted therapies that affect multiple signaling pathways and stimulate antitumor immunity is greatly needed. About 20% of patients with breast cancer overexpress HER2. Small molecules and antibodies targeting HER2 convey some survival benefits; however, patients with advanced disease succumb to the disease under these treatment regimens, possibly because HER2 is not completely necessary for the survival of the targeted cancer cells. In the present study, we show that a polyinosine/polycytosine (pIC) HER2-homing chemical vector induced the demise of HER2-overexpressing breast cancer cells, including trastuzumab-resistant cells. Targeting pIC to the tumor evoked a number of cell-killing mechanisms, as well as strong bystander effects. These bystander mechanisms included type I IFN induction, immune cell recruitment, and activation. The HER2-targeted pIC strongly inhibited the growth of HER2-overexpressing tumors in immunocompetent mice. The data presented here could open additional avenues in the treatment of HER2-positive breast cancer. Cancer Immunol Res; 4(8); 688-97. ©2016 AACR.
authors.affiliation: Unit of Cellular Signaling, Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Zigler
authors.affiliation: Unit of Cellular Signaling, Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Alexei
authors.initials: A
authors.lastname: Shir
authors.affiliation: Unit of Cellular Signaling, Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Salim
authors.initials: S
authors.lastname: Joubran
authors.affiliation: Unit of Cellular Signaling, Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Sagalov
authors.affiliation: Unit of Cellular Signaling, Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Shoshana
authors.initials: S
authors.lastname: Klein
authors.affiliation: Unit of Cellular Signaling, Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Nufar
authors.initials: N
authors.lastname: Edinger
authors.affiliation: Translational Oncology Department, Genentech Inc., South San Francisco, California.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lau
authors.affiliation: Translational Oncology Department, Genentech Inc., South San Francisco, California.
authors.forename: Shang-Fan
authors.initials: SF
authors.lastname: Yu
authors.affiliation: Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University, Jerusalem, Israel.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mizraji
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovoth, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Globerson Levin
authors.affiliation: Molecular Oncology Department, Genentech, Inc. South San Francisco, California.
authors.forename: Mark X
authors.initials: MX
authors.lastname: Sliwkowski
authors.affiliation: Unit of Cellular Signaling, Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel. alex.levitzki@mail.huji.ac.il.
authors.forename: Alexander
authors.initials: A
authors.lastname: Levitzki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D011070:Poly I-C / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000235:genetics / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D018836:Inflammation Mediators; D011070:Poly I-C; D018719:Erb-b2 Receptor Tyrosine Kinases