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    Enhanced radiation sensitivity in HPV-positive head and neck cancer

    Mon, Jun 10, 2013

    Oral Cancer News

    Source: http://cancerres.aacrjournals.org
    Authors: 
    Randall J. Kimple1,*,Molly A. Smith1,Grace C Blitzer1,Alexandra D Torres1,Joshua A Martin1,Robert Z. Yang1,Chimera R Peet1,Laurel D. Lorenz2,Kwangok P Nickel3,Aloysius J Klingelhutz4,Paul F Lambert5, andPaul M Harari1

     

    Abstract

    Patients with human papillomavirus associated (HPV+) head and neck cancer (HNC) demonstrate significantly improved survival outcome compared to those with HPV-negative (HPV-) tumors. Published data examining this difference offers conflicting results to date. We systematically investigated the radiation sensitivity of all available validated HPV+ HNC cell lines and a series of HPV- HNC cell lines using in vitro and in vivo techniques. HPV+ HNCs exhibited greater intrinsic radiation sensitivity (average SF2 HPV- 0.59 vs. HPV+ 0.22, p<0.0001), corresponding with a prolonged G2/M cell cycle arrest and increased apoptosis following radiation exposure (percent change 0% vs. 85%, p=0.002). A genome-wide microarray was used to compare gene-expression 24 hours following radiation between HPV+ and HPV- cell lines. Multiple genes in TP53 pathway were upregulated in HPV+ cells (Z score 4.90), including a 4.6 fold increase in TP53 (p<0.0001). Using immortalized human tonsillar epithelial cells, increased radiation sensitivity was seen in cell expressing HPV-16 E6 despite the effect of E6 to degrade p53. This suggested that low levels of normally functioning p53 in HPV+ HNC cells could be activated by radiation, leading to cell death. Consistent with this, more complete knockdown of TP53 by siRNA resulted in radiation resistance. These results provide clear evidence, and a supporting mechanism, for increased radiation sensitivity in HPV+ HNC relative to HPV- HNC. This issue is under active investigation in a series of clinical trials attempting to de-escalate radiation (and chemotherapy) in selected patients with HPV+ HNC in light of their favorable overall survival outcome.

    • Received February 28, 2013.
    • Revision received April 9, 2013.
    • Accepted April 26, 2013.
     

    • Copyright © 2013, American Association for Cancer Research.

     

    *This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

     

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