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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
5T4-targeted therapy ablates cancer stem cells and prevents recurrence of head and neck squamous cell carcinoma
Clinical Cancer Research, Volume 23, No. 10, Year 2017
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Description
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. ©2016 AACR.
Authors & Co-Authors
Kerk, Samuel Andrew
United States, Ann Arbor
University of Michigan School of Dentistry
Pearson, Alexander T.
United States, Ann Arbor
University of Michigan School of Dentistry
United States, Ann Arbor
Michigan Medicine
United States, Ann Arbor
University of Michigan, Ann Arbor
Wagner, Vivian Petersen
Brazil, Porto Alegre
Universidade Federal do Rio Grande do Sul
United States, Ann Arbor
University of Michigan School of Dentistry
Vargas, P. A.
Brazil, Campinas
Universidade Estadual de Campinas
Wicha, Max S.
United States, Ann Arbor
Michigan Medicine
United States, Ann Arbor
University of Michigan, Ann Arbor
Statistics
Citations: 34
Authors: 5
Affiliations: 7
Identifiers
Doi:
10.1158/1078-0432.CCR-16-1834
ISSN:
10780432
Research Areas
Cancer
Genetics And Genomics
Health System And Policy
Study Design
Randomised Control Trial
Cohort Study