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Spotlight on Clinical Response

p53 therapy in a patient with Li-Fraumeni syndrome

¹ Mary Crowley Medical Research Center; ² Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas; ³ The Royal Marsden Hospital NHS Foundation Trust; ⁴ Imperial College London Hammersmith Campus, London, United Kingdom; ⁵ Institute of Cancer Research, Sutton, United Kingdom; ⁶ Qualtek, Inc., Newtown, Pennsylvania; and ⁷ Introgen Therapeutics, Inc., Houston, Texas

Requests for reprints: John Nemunaitis, Mary Crowley Medical Research Center, 60th Floor, 1717 Main Street, Dallas, TX 75201. Phone: 214-658-1964; Fax: 214-658-1992. E-mail: jnemunaitis{at}mcmrc.com

Abstract

Li-Fraumeni syndrome is an autosomal dominant disorder that greatly increases the risk of developing multiple types of cancer. The majority of Li-Fraumeni syndrome families contain germ-line mutations in the p53 tumor suppressor gene. We describe treatment of a refractory, progressive Li-Fraumeni syndrome embryonal carcinoma with a p53 therapy (Advexin) targeted to the underlying molecular defect of this syndrome. p53 treatment resulted in complete and durable remission of the injected lesion by fluorodeoxyglucose-positron emission tomography scans with improvement of tumor-related symptoms. With respect to molecular markers, the patient's tumor had abnormal p53 and expressed coxsackie adenovirus receptors with a low HDM2 and bcl-2 profile conducive for adenoviral p53 activity. p53 treatment resulted in the induction of cell cycle arrest and apoptosis documented by p21 and cleaved caspase-3 detection. Increased adenoviral antibody titers after repeated therapy did not inhibit adenoviral p53 activity or result in pathologic sequelae. Relationships between these clinical, radiographic, and molecular markers may prove useful in guiding future application of p53 tumor suppressor therapy. [Mol Cancer Ther 2007;6(5):1478–1482

Grant support: Introgen Therapeutics, Inc.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: R.E. Sobol and S. Chada contributed equally to this work.

Received 2/23/07; accepted 3/30/07.

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