This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rubio-Viqueira, B. Articles by Altiok, S. Search for Related Content PubMed PubMed Citation Articles by Rubio-Viqueira, B. Articles by Altiok, S.

Research Articles: Therapeutics, Targets, and Development

Optimizing the development of targeted agents in pancreatic cancer: tumor fine-needle aspiration biopsy as a platform for novel prospective ex vivo drug sensitivity assays

¹ Sidney Kimmel Comprehensive Cancer Center and The Sol Goldman Pancreatic Cancer Research Center at Johns Hopkins and Departments of ² Oncology, ³ Pathology, and ⁴ Urology, The Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Soner Altiok, Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287. Phone: 443-287-4638; Fax: 410-614-9556. E-mail: saltiok1{at}jhmi.edu

Abstract

At the present time, the optimal development of molecularly targeted anticancer agents is limited by the lack of clinically applicable tools to predict drug effects. This study aimed to develop methods that might be useful in predicting the efficacy of targeted agents in a novel model system of human pancreatic cancer. A series of xenografts were established in nude mice by implanting human pancreatic cancer tissue surgically resected from cancer patients. Animals were treated with the epidermal growth factor receptor inhibitor erlotinib, the mammalian target of rapamycin inhibitor temsirolimus, or vehicle. Tumor cells were sampled by fine-needle aspiration biopsy (FNAB) before (baseline, day 0) and at the completion of 28 days of treatment. Cells obtained at baseline were exposed to erlotinib or temsirolimus in short-term cell culture conditions (ex vivo). Western blot analysis was done to determine the degree of inhibition in the phosphorylation of extracellular signal-regulated kinase 1/2 and S6-ribosomal protein (downstream effectors of epidermal growth factor receptor and mammalian target of rapamycin, respectively) ex vivo and in vivo. Five of six xenografted tumors responded to temsirolimus, whereas only one tumor responded to erlotinib. The results of the ex vivo studies correctly predicted the pharmacodynamic effect of the agents in vivo as well as their gross antitumor effects. Finally, we showed the clinical feasibility of this approach, performing ex vivo assessment of drug-target response in FNAB samples from three patients with pancreatic cancer. Cancer cells obtained by FNAB, an established minimally invasive diagnostic procedure, can be used to test ex vivo the effects of targeted anticancer agents. These effects correlate with antitumor activity in vivo and may therefore provide an important tool applicable to clinical trials. Ultimately, an approach of this nature may facilitate the further refinement of patient selection in favor of individuals with molecular profiles, predicting a greater likelihood of therapeutic benefit. [Mol Cancer Ther 2007;6(2):515–23]

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.

Received 7/ 5/06; revised 11/ 3/06; accepted 12/ 5/06.

This article has been cited by other articles:

				J. Nieto, M. L. Grossbard, and P. Kozuch Metastatic Pancreatic Cancer 2008: Is the Glass Less Empty? Oncologist, May 1, 2008; 13(5): 562 - 576. [Abstract] [Full Text] [PDF]

				S. A. Lang, C. Moser, A. Gaumann, D. Klein, G. Glockzin, F. C. Popp, M. H. Dahlke, P. Piso, H. J. Schlitt, E. K. Geissler, et al. Targeting Heat Shock Protein 90 in Pancreatic Cancer Impairs Insulin-like Growth Factor-I Receptor Signaling, Disrupts an Interleukin-6/Signal-Transducer and Activator of Transcription 3/Hypoxia-Inducible Factor-1{alpha} Autocrine Loop, and Reduces Orthotopic Tumor Growth Clin. Cancer Res., November 1, 2007; 13(21): 6459 - 6468. [Abstract] [Full Text] [PDF]