Volume 7 Supplement 2

São Paulo Advanced School of Comparative Oncology: Abstracts

Open Access

Targeting uroporphyrinogen decarboxylase for head and neck cancer treatment

  • Emma Ito1, 2Email author,
  • Shijun Yue2,
  • Eduardo H Moriyama1,
  • Angela B Hui2,
  • Inki Kim2,
  • Wei Shi2,
  • Nehad M Alajez2,
  • Nirmal Bhogal2,
  • GuoHua Li3,
  • Alessandro Datti4, 5,
  • Aaron D Schimmer1, 2,
  • Brian C Wilson1,
  • Peter P Liu3,
  • Daniel Durocher4,
  • Benjamin G Neel1, 2,
  • Brian O’Sullivan6, 7,
  • Bernard Cummings6, 7,
  • Rob Bristow1, 2, 6, 7,
  • Jeff Wrana4 and
  • Fei-Fei Liu1, 2, 6, 7
BMC Proceedings20137(Suppl 2):P19

DOI: 10.1186/1753-6561-7-S2-P19

Published: 4 April 2013

Background

Head and neck cancer (HNC) is the 8th most common malignancy worldwide. Despite advances in therapeutic options over the last few decades, treatment toxicities and overall clinical outcomes have remained disappointing, underscoring a need to develop novel therapeutic approaches, particularly those that enhance tumor cell death, while minimizing damage to the surrounding normal tissues.

Materials and methods

An RNA interference (RNAi)-based high-throughput screen (HTS) was performed for the large-scale identification of novel genes that will selectively sensitize HNC cells to ionizing radiation. The Dharmacon Protein Kinase and Druggable Genome siRNA Libraries were screened using FaDu cells (human hypopharyngeal squamous cell cancer). Radiosensitizing targets were subjected to in vitro and in vivo characterizations.

Results

Sixty-seven target sequences with potential radiosensitizing effects were identified. Targets reducing the surviving fraction by >50% at 2 Gy relative to their un-irradiated counterparts were selected for further evaluation. A key regulator of heme biosynthesis, uroporphyrinogen decarboxylase (UROD), was thereby identified as a novel tumor-selective radiosensitizing target, demonstrating both in vitro and in vivo efficacy. Radiosensitization appeared to be mediated via enhancement of tumor oxidative stress from perturbation of iron homeostasis and increased free radical production. UROD was significantly over-expressed in HNC patient biopsies, wherein lower pre-radiation mRNA levels correlated with improved survival, suggesting UROD could potentially predict radiation response. UROD down-regulation also radiosensitized several different human cancer models, while sparing normal cells.

Conclusions

An RNAi-based radiosensitizer HTS has revealed UROD as a potent tumor-selective sensitizer for radiation, with potential relevance to many human malignancies.

Financial support

Canadian Institutes of Health Research (CIHR; grant 69023); Elia Chair in Head and Neck Cancer Research; philanthropic support from Wharton Family, J. Finley, and G. Tozer; Campbell Family Institute for Cancer Research; Ministry of Health and Long-Term Planning; CIHR Resource Maintenance grant (PRG-82679).

Authors’ Affiliations

(1)
Department of Medical Biophysics, University of Toronto
(2)
Ontario Cancer Institute, Campbell Family Cancer Research Institute, University Health Network
(3)
Toronto General Research Institute, University Health Network
(4)
Samuel Lunenfeld Research Institute, Mount Sinai Hospital
(5)
Department of Experimental Medicine and Biochemical Sciences, University of Perugia
(6)
Department of Radiation Oncology, Princess Margaret Hospital, University Health Network
(7)
Department of Radiation Oncology, University of Toronto

Copyright

© Ito et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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