title: 5T4-Targeted Therapy Ablates Cancer Stem Cells and Prevents Recurrence of Head and Neck Squamous Cell Carcinoma.
abstract: Purpose:Locoregional recurrence is a frequent treatment outcome for patients with advanced head and neck squamous cell carcinoma (HNSCC). Emerging evidence suggests that tumor recurrence is mediated by a small subpopulation of uniquely tumorigenic cells, that is, cancer stem cells (CSC), that are resistant to conventional chemotherapy, endowed with self-renewal and multipotency.Experimental Design:Here, we evaluated the efficacy of MEDI0641, a novel antibody-drug conjugate targeted to 5T4 and carrying a DNA-damaging "payload" (pyrrolobenzodiazepine) in preclinical models of HNSCC.Results:Analysis of a tissue microarray containing 77 HNSCC with follow-up of up to 12 years revealed that patients with 5T4hightumors displayed lower overall survival than those with 5T4lowtumors (P= 0.038). 5T4 is more highly expressed in head and neck CSC (ALDHhighCD44high) than in control cells (non-CSC). Treatment with MEDI0641 caused a significant reduction in the CSC fraction in HNSCC cells (UM-SCC-11B, UM-SCC-22B)in vitroNotably, a single intravenous dose of 1 mg/kg MEDI0641 caused long-lasting tumor regression in three patient-derived xenograft (PDX) models of HNSCC. MEDI0641 ablated CSC in the PDX-SCC-M0 model, reduced it by five-fold in the PDX-SCC-M1, and two-fold in the PDX-SCC-M11 model. Importantly, mice (n= 12) treated with neoadjuvant, single administration of MEDI0641 prior to surgical tumor removal showed no recurrence for more than 200 days, whereas the control group had 7 recurrences (in 12 mice;P= 0.0047).Conclusions:Collectively, these findings demonstrate that an anti-5T4 antibody-drug conjugate reduces the fraction of CSCs and prevents local recurrence and suggest a novel therapeutic approach for patients with HNSCC.Clin Cancer Res; 23(10); 2516-27. ©2016 AACR.
authors: Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan.
authors: Samuel A
authors: SA
authors: Kerk
authors: Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan.
authors: Kelsey A
authors: KA
authors: Finkel
authors: Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan.|Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors: Alexander T
authors: AT
authors: Pearson
authors: Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan.
authors: Kristy A
authors: KA
authors: Warner
authors: Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan.
authors: Zhaocheng
authors: Z
authors: Zhang
authors: Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan.|Department of Oral Pathology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
authors: Felipe
authors: F
authors: Nör
authors: Department of Oral Pathology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.|Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan.
authors: Vivian P
authors: VP
authors: Wagner
authors: Department of Oral Diagnosis, University of Campinas, Piracicaba, Brazil.
authors: Pablo A
authors: PA
authors: Vargas
authors: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors: Max S
authors: MS
authors: Wicha
authors: Oncology Research, MedImmune, Gaithersburg, Maryland.
authors: Elaine M
authors: EM
authors: Hurt
authors: Oncology Research, MedImmune, Gaithersburg, Maryland.
authors: Robert E
authors: RE
authors: Hollingsworth
authors: Oncology Research, MedImmune, Gaithersburg, Maryland.
authors: David A
authors: DA
authors: Tice
authors: Department of Cariology, Restorative Sciences, Endodontics, University of Michigan School of Dentistry, Ann Arbor, Michigan. jenor@umich.edu.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, Michigan.|Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, Michigan.
authors: Jacques E
authors: JE
authors: Nör
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000008:administration & dosage; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal / Q000235:genetics / Q000276:immunology; D004249:DNA Damage / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D011758:Pyrroles / Q000008:administration & dosage; D000077195:Squamous Cell Carcinoma of Head and Neck; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D011758:Pyrroles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; C063709:trophoblastic glycoprotein 5T4, human; D001569:Benzodiazepines