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Credentialing Preclinical Pediatric Xenograft Models Using Gene Expression and Tissue Microarray Analysis

¹ Oncogenomics Section, ² Comparative Oncology Program, and ³ Cell and Molecular Biology Section, Pediatric Oncology Branch; ⁴ Tissue Array Research Program, Laboratory of Pathology; and ⁵ Cancer Therapy Evaluation Program, National Cancer Institute, NIH, Bethesda, Maryland; ⁶ St. Jude Children's Research Hospital Memphis, Memphis, Tennessee; ⁷ Developmental Therapeutics Program, USC-CHLA, Institute for Pediatric Clinical Research, Children's Hospital Los Angeles, Los Angeles, California; ⁸ Leukaemia Biology Program, Children's Cancer Institute Australia for Medical Research, Sydney, New South Wales, Australia; ⁹ Section of Hematology/Oncology, The Children's Hospital at Montefiore, Bronx, New York; and ¹⁰ Tumour Bank, The Children's Hospital at Westmead, Westmead, New South Wales, Australia

Requests for reprints: Javed Khan, Oncogenomics Section, Pediatric Oncology Branch, National Cancer Institute, NIH, Room 134E, 8717 Grovemont Circle, Bethesda, MD 20892-4605. Phone: 301-435-2937; Fax: 301-480-0341; E-mail: khanjav{at}mail.nih.gov.

Human tumor xenografts have been used extensively for rapid screening of the efficacy of anticancer drugs for the past 35 years. The selection of appropriate xenograft models for drug testing has been largely empirical and has not incorporated a similarity to the tumor type of origin at the molecular level. This study is the first comprehensive analysis of the transcriptome of a large set of pediatric xenografts, which are currently used for preclinical drug testing. Suitable models representing the tumor type of origin were identified. It was found that the characteristic expression patterns of the primary tumors were maintained in the corresponding xenografts for the majority of samples. Because a prerequisite for developing rationally designed drugs is that the target is expressed at the protein level, we developed tissue arrays from these xenografts and corroborated that high mRNA levels yielded high protein levels for two tested genes. The web database and availability of tissue arrays will allow for the rapid confirmation of the expression of potential targets at both the mRNA and the protein level for molecularly targeted agents. The database will facilitate the identification of tumor markers predictive of response to tested agents as well as the discovery of new molecular targets. [Cancer Res 2007;67(1):32–40]

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