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 5T4high tumors displayed lower overall survival than those with 5T4low tumors (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 vitro Notably, 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: Samuel A Kerk, Kelsey A Finkel, Alexander T Pearson, Kristy A Warner, Zhaocheng Zhang, Felipe Nör, Vivian P Wagner, Pablo A Vargas, Max S Wicha, Elaine M Hurt, Robert E Hollingsworth, David A Tice, Jacques E Nör
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 10 Pg. 2516-2527 (May 15 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 27780858 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Immunoconjugates
• Membrane Glycoproteins
• Pyrroles
• pyrrolo(2,1-c)(1,4)benzodiazepine
• trophoblastic glycoprotein 5T4, human
• Benzodiazepines

Topics

• Animals
• Benzodiazepines (administration & dosage)
• Carcinoma, Squamous Cell (drug therapy, pathology)
• Cell Line, Tumor
• Cell Self Renewal (genetics, immunology)
• DNA Damage (drug effects)
• Drug Resistance, Neoplasm (immunology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Head and Neck Neoplasms (drug therapy, pathology)
• Humans
• Immunoconjugates (administration & dosage, immunology)
• Membrane Glycoproteins (immunology)
• Mice
• Neoplasm Recurrence, Local (drug therapy, immunology, pathology)
• Neoplastic Stem Cells (drug effects, immunology, pathology)
• Pyrroles (administration & dosage)
• Squamous Cell Carcinoma of Head and Neck
• Tissue Array Analysis
• Treatment Outcome
• Xenograft Model Antitumor Assays