Intratumoral Epidermal Growth Factor Receptor Antisense DNA Therapy in Head and Neck Cancer: First Human Application and Potential Antitumor Mechanisms

Lai, Stephen Y.; Koppikar, Priya; Thomas, Sufi M.; Childs, Erin E.; Egloff, Ann Marie; Seethala, Raja R.; Branstetter, Barton F.; Gooding, William E.; Muthukrishnan, Ashok; Mountz, James M.; Lui, Vivian Wai Yan; Shin, Dong M.; Agarwala, Sanjiv S.; Johnson, Rita; Couture, Larry A.; Myers, Eugene N.; Johnson, Jonas T.; Mills, Gordon B.; Argiris, Athanassios; Grandis, Jennifer R.

doi:10.1200/jco.2008.17.8251

Cited by 62 publications

(54 citation statements)

References 29 publications

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“…In a cohort of twenty patients, no grade 3 or 4 toxicities were reported. In addition, median survival was 5.4 months [85]. The disease-control group, as defined by complete remission, partial remission, or stable disease, demonstrated a median survival of 7.9 months as compared to 3.4 months for the partial disease group [85].…”

Section: Antisense Oligonucleotides and Sirnamentioning

confidence: 99%

Investigational EGFR-targeted therapy in head and neck squamous cell carcinoma

Cassell

Grandis²

2010

Expert Opinion on Investigational Drugs

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Importance of the Field The epidermal growth factor receptor (EGFR) is an established therapeutic target in head and neck squamous cell carcinoma (HNSCC). The EGFR-targeting monoclonal antibody cetuximab (™Erbitux) was FDA-approved for use in HNSCC in 2006. The molecular basis for the efficacy of an antibody approach compared with inhibition of EGFR tyrosine kinase function using small molecule inhibitors, or downregulation of protein expression via antisense strategies remains incompletely understood. Areas covered in this review A literature search was performed to identify studies elucidating mechanisms of action of several approaches to targeting EGFR in HNSCC (monoclonal antibodies, tyrosine kinase inhibitors, antisense approaches, and ligand toxin conjugates). What the reader will gain Monoclonal antibodies decrease tumor growth via receptor endocytosis and recruitment of host immune defenses. Tyrosine kinase inhibitors bind to the ATP binding pocket of the tyrosine kinase domain, inhibiting signaling. Antisense approaches decrease EGFR expression with high specificity although drug delivery remains problematic. Ligand-toxin conjugates facilitate the entry of toxin and the ADP-ribosylation of the ribosome, thereby inhibiting translation. Take home message Elucidation mechanisms by which these different strategies inhibit EGFR function may enhance the development of more effective treatments for HNSCC and enable prospective identification of individuals who will benefit from EGFR inhibition.

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Section: Antisense Oligonucleotides and Sirnamentioning

confidence: 99%

Investigational EGFR-targeted therapy in head and neck squamous cell carcinoma

Cassell

Grandis²

2010

Expert Opinion on Investigational Drugs

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“…Plasmid DNA encoding an EGFR antisense fragment was injected intratumorally into HNSCC xenografts, resulting in antitumor effects (He et al, 1998). On the basis of these studies a dose escalation phase I clinical trial was carried out with intratumoral administration of the EGFR antisense plasmid DNA (Lai et al, 2009). No dose-limiting toxicity was observed at any of the doses.…”

Section: Gene Excision Therapymentioning

confidence: 99%

The Current State of Head and Neck Cancer Gene Therapy

Thomas

Grandis²

2009

Human Gene Therapy

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The incidence of head and neck cancer continues to increase worldwide, with tobacco exposure and human papillomavirus type 16 infections being the major etiological factors. Current therapeutic options are ineffective in approximately half of the individuals afflicted with this malignancy. Developments in the identification of molecules that sustain head and neck squamous cell carcinoma (HNSCC) growth and survival have made molecular targeting by gene therapy approaches a feasible therapeutic strategy. Although gene therapy was originally designed to correct single gene defects, it has now evolved to encompass all forms of therapeutic interventions involving engineered cells and nucleic acids that modify the overall pattern of gene expression within target tissues. Several preclinical studies and clinical trials have tested the efficacy of targeting specific molecules in patients with HNSCC, using genetic therapy approaches. This review discusses promising preclinical and clinical approaches and new directions for HNSCC gene therapy.

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“…Results from a phase I trial using local delivery of a plasmid encoding antisense RNA against the EGFR to treat HNSCC have been published recently (Lai et al, 2009). Although these findings need to be borne out in larger trials, they showed a 30% response rate (versus 10-15% response to other anti-EGFR therapies).…”

Section: Prodrug Sensitizationmentioning

confidence: 94%