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Research Articles: Therapeutics, Targets, and Development

LY2109761, a novel transforming growth factor β receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis

¹ Department of Gastrointestinal Medical Oncology and ² Surgical Oncology and Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center; ³ Program of Cancer Biology, Graduate School of Biomedical Sciences, University of Texas-Houston Health Science Center, Houston, Texas; and ⁴ Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università di Napoli "Federico II," Naples, Italy

Requests for reprints: Paul J. Chiao, Department of Surgical Oncology, Unit 107, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-794-1030; Fax: 713-794-4830. E-mail: pjchiao{at}mdanderson.org

Abstract

Most pancreatic cancer patients present with inoperable disease or develop metastases after surgery. Conventional therapies are usually ineffective in treating metastatic disease. It is evident that novel therapies remain to be developed. Transforming growth factor β (TGF-β) plays a key role in cancer metastasis, signaling through the TGF-β type I/II receptors (TβRI/II). We hypothesized that targeting TβRI/II kinase activity with the novel inhibitor LY2109761 would suppress pancreatic cancer metastatic processes. The effect of LY2109761 has been evaluated on soft agar growth, migration, invasion using a fibroblast coculture model, and detachment-induced apoptosis (anoikis) by Annexin V flow cytometric analysis. The efficacy of LY2109761 on tumor growth, survival, and reduction of spontaneous metastasis have been evaluated in an orthotopic murine model of metastatic pancreatic cancer expressing both luciferase and green fluorescence proteins (L3.6pl/GLT). To determine whether pancreatic cancer cells or the cells in the liver microenvironment were involved in LY2109761-mediated reduction of liver metastasis, we used a model of experimental liver metastasis. LY2109761 significantly inhibited the L3.6pl/GLT soft agar growth, suppressed both basal and TGF-β1–induced cell migration and invasion, and induced anoikis. In vivo, LY2109761, in combination with gemcitabine, significantly reduced the tumor burden, prolonged survival, and reduced spontaneous abdominal metastases. Results from the experimental liver metastasis models indicate an important role for targeting TβRI/II kinase activity on tumor and liver microenvironment cells in suppressing liver metastasis. Targeting TβRI/II kinase activity on pancreatic cancer cells or the cells of the liver microenvironment represents a novel therapeutic approach to prevent pancreatic cancer metastasis. [Mol Cancer Ther 2008;7(4):829–40]

Grant support: U.S. Public Services grants R01CA097159 (P.J. Chiao) and P20-CA101936 (J.L. Abbruzzese), Cancer Center Supporting grant from National Cancer Institute, Lockton Fund for Pancreatic Cancer Research grants (P.J. Chiao), and Topfer Fund for Pancreatic Cancer Research (J.L. Abbruzzese and P.J. Chiao). D. Melisi was recipient of an AIRC-FIRC "Leonino Fontana e Maria Lionello 2005" award and a "Marion D. Edward 2007" award.

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.

⁵ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

⁶ Jonathan M. Yingling, Eli Lilly, unpublished data.

Received 5/14/07; revised 1/ 8/08; accepted 2/28/08.