Clin Cancer Res. 2016 Oct 25. pii: clincanres.1834.2016. [Epub ahead of print] 5T4-targeted therapy ablates cancer stem cells and prevents recurrence of head and neck squamous cell carcinoma. Kerk S1, Finkel K2, Pearson AT3, Warner K4, Nor F1, Zhang Z5, Wagner VP6, Vargas PA7, Wicha MS8, Hurt E9, Hollingsworth RE10, Tice DA11, Nor JE12. Author information 1Cariology, Restorative Sciences and Endodontics, University of Michigan School of Dentistry. 2Department of Restorative Sciences, University of Michigan School of Dentistry. 3Internal Medicine, University of Michigan Medical Center. 4Dentistry, University of Michigan. 5Restorative Sciences, University of Michigan. 6Periodontics and Oral Medicine, University of Michigan School of Dentistry. 7Oral Diagnosis, UNICAMP. 8Department of Internal Medicine, University of Michigan. 9Cancer Biology, MedImmune LLC. 10Oncology Research, MedImmune, Inc. 11Oncology Research, Medimmune. 12Dentistry, University of Michigan jenor@umich.edu. Abstract PURPOSE: Loco-regional 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, i.e. 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 3 patient-derived xenograft (PDX) models of HNSCC. MEDI0641 ablated CSC in the PDX-SCC-M0 model, reduced it by 5-fold in the PDX-SCC-M1, and 2-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 over 200 days, while 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 cancer stem cells and prevents local recurrence, and suggest a novel therapeutic approach for patients with HNSCC.
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