Combining agents that target the tumor microenvironment improves the efficacy of anticancer therapy

Joseph A. Blansfield, Diana Caragacianu, H. Richard Alexander, Michael A. Tangrea, Shane Y. Morita, Dominique Lorang, Peter Schafer, George Muller, David Stirling, Richard E. Royal, Steven K. Libutti

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

Purpose: Over the past 60 years, cytotoxic chemotherapy has targeted the cancer cell. Despite this, there have been few cancer cures. A new approach to cancer therapy is to target the multicellular biological entity of the tumor microenvironment. Experimental Design: Lenalidomide, an immunomodulatory drug, sunitinib, a tyrosine kinase inhibitor, and low-dose metronomic cyclophosphamide, were tested alone and in combination for their abilities to inhibit endothelial cell tube formation, rat aortic ring outgrowth, tumor growth, and metastatic development in mice. In addition, ectopic tumor lysates were evaluated for the presence of proangiogenic proteins. Results: The three agents alone were shown to significantly inhibit endothelial cells' ability to form tubes and significantly inhibit the multicellular microenvironment in the rat aortic ring assay (P < 0.01 and P < 0.001). This effect was also significantly augmented when the agents were combined. Furthermore, the three-drug combination was able halt the progression of tumor growth almost completely in xenograft models of ocular melanoma, colon cancer, pancreatic cancer, and cutaneous melanoma. These agents significantly decrease the number of proliferating cells in tumors, significantly increase the number of cells undergoing active cell death in tumors, and significantly decrease the number of blood vessels in treated tumors (P < 0.05). Combination therapy shows a decrease in the compensatory up-regulation of proangiogenic proteins after treatment when compared with single-agentt herapy. Conclusions: This combination of agents causes an in hospitable microenvironment for tumor cells and shows great promise for use in the clinic.

Original languageEnglish (US)
Pages (from-to)270-280
Number of pages11
JournalClinical Cancer Research
Volume14
Issue number1
DOIs
StatePublished - Jan 1 2008
Externally publishedYes

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Tumor Microenvironment
Neoplasms
Therapeutics
Melanoma
Endothelial Cells
Cell Count
Cellular Microenvironment
Skin Neoplasms
Drug Combinations
Pancreatic Neoplasms
Growth and Development
Heterografts
Protein-Tyrosine Kinases
Colonic Neoplasms
Cyclophosphamide
Blood Vessels
Proteins
Cell Death
Research Design
Up-Regulation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Blansfield, J. A., Caragacianu, D., Alexander, H. R., Tangrea, M. A., Morita, S. Y., Lorang, D., ... Libutti, S. K. (2008). Combining agents that target the tumor microenvironment improves the efficacy of anticancer therapy. Clinical Cancer Research, 14(1), 270-280. https://doi.org/10.1158/1078-0432.CCR-07-1562

Combining agents that target the tumor microenvironment improves the efficacy of anticancer therapy. / Blansfield, Joseph A.; Caragacianu, Diana; Alexander, H. Richard; Tangrea, Michael A.; Morita, Shane Y.; Lorang, Dominique; Schafer, Peter; Muller, George; Stirling, David; Royal, Richard E.; Libutti, Steven K.

In: Clinical Cancer Research, Vol. 14, No. 1, 01.01.2008, p. 270-280.

Research output: Contribution to journalArticle

Blansfield, JA, Caragacianu, D, Alexander, HR, Tangrea, MA, Morita, SY, Lorang, D, Schafer, P, Muller, G, Stirling, D, Royal, RE & Libutti, SK 2008, 'Combining agents that target the tumor microenvironment improves the efficacy of anticancer therapy', Clinical Cancer Research, vol. 14, no. 1, pp. 270-280. https://doi.org/10.1158/1078-0432.CCR-07-1562
Blansfield JA, Caragacianu D, Alexander HR, Tangrea MA, Morita SY, Lorang D et al. Combining agents that target the tumor microenvironment improves the efficacy of anticancer therapy. Clinical Cancer Research. 2008 Jan 1;14(1):270-280. https://doi.org/10.1158/1078-0432.CCR-07-1562
Blansfield, Joseph A. ; Caragacianu, Diana ; Alexander, H. Richard ; Tangrea, Michael A. ; Morita, Shane Y. ; Lorang, Dominique ; Schafer, Peter ; Muller, George ; Stirling, David ; Royal, Richard E. ; Libutti, Steven K. / Combining agents that target the tumor microenvironment improves the efficacy of anticancer therapy. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 1. pp. 270-280.
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