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

Publication ,  Journal Article
Melisi, D; Ishiyama, S; Sclabas, GM; Fleming, JB; Xia, Q; Tortora, G; Abbruzzese, JL; Chiao, PJ
Published in: Mol Cancer Ther
April 2008

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 beta (TGF-beta) plays a key role in cancer metastasis, signaling through the TGF-beta type I/II receptors (TbetaRI/II). We hypothesized that targeting TbetaRI/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-beta1-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 TbetaRI/II kinase activity on tumor and liver microenvironment cells in suppressing liver metastasis. Targeting TbetaRI/II kinase activity on pancreatic cancer cells or the cells of the liver microenvironment represents a novel therapeutic approach to prevent pancreatic cancer metastasis.

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Published In

Mol Cancer Ther

DOI

ISSN

1535-7163

Publication Date

April 2008

Volume

7

Issue

4

Start / End Page

829 / 840

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Transforming Growth Factor beta
  • Survival Rate
  • Smad2 Protein
  • Signal Transduction
  • Ribonucleotide Reductases
  • Receptors, Transforming Growth Factor beta
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptor, Transforming Growth Factor-beta Type I
 

Citation

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Melisi, D., Ishiyama, S., Sclabas, G. M., Fleming, J. B., Xia, Q., Tortora, G., … Chiao, P. J. (2008). LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther, 7(4), 829–840. https://doi.org/10.1158/1535-7163.MCT-07-0337
Melisi, Davide, Satoshi Ishiyama, Guido M. Sclabas, Jason B. Fleming, Qianghua Xia, Giampaolo Tortora, James L. Abbruzzese, and Paul J. Chiao. “LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis.Mol Cancer Ther 7, no. 4 (April 2008): 829–40. https://doi.org/10.1158/1535-7163.MCT-07-0337.
Melisi D, Ishiyama S, Sclabas GM, Fleming JB, Xia Q, Tortora G, et al. LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther. 2008 Apr;7(4):829–40.
Melisi, Davide, et al. “LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis.Mol Cancer Ther, vol. 7, no. 4, Apr. 2008, pp. 829–40. Pubmed, doi:10.1158/1535-7163.MCT-07-0337.
Melisi D, Ishiyama S, Sclabas GM, Fleming JB, Xia Q, Tortora G, Abbruzzese JL, Chiao PJ. LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther. 2008 Apr;7(4):829–840.

Published In

Mol Cancer Ther

DOI

ISSN

1535-7163

Publication Date

April 2008

Volume

7

Issue

4

Start / End Page

829 / 840

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Transforming Growth Factor beta
  • Survival Rate
  • Smad2 Protein
  • Signal Transduction
  • Ribonucleotide Reductases
  • Receptors, Transforming Growth Factor beta
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptor, Transforming Growth Factor-beta Type I