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Lymphoma

Targeting the mammalian target of Rapamycin to inhibit VEGF and cytokines for the treatment of primary effusion lymphoma

Leukemia volume 23, pages 1867–1874 (2009)Cite this article

Abstract

Primary effusion lymphoma (PEL) is a fatal malignancy, which typically presents as a lymphomatous effusion that later disseminates. Rapamycin (Rapa), which targets mTOR (mammalian target of Rapa), is currently evaluated as a treatment for PEL, but the recent development of PEL in Rapa-treated post-transplant recipients questions the drug's use in PEL. Here, we used a murine model of PEL effusion that mimics the human disease to investigate the anti-PEL activity of Rapa. We found that Rapa reduces ascites accumulation and extends mouse survival. Initially, Rapa reduced PEL load compared with control mice, but most mice rapidly showed PEL progression. Levels of VEGF, which promotes vascular permeability contributing to effusion formation, were significantly reduced in ascites of Rapa-treated mice compared with controls. Expression of IL-10, the principal autocrine growth factor for PEL, was initially reduced in PEL from Rapa-treated mice but rapidly increased despite treatment. We found that the hypoxic environment of ascites and Rapa cooperate in stimulating IL-10 expression in PEL, which likely contributes to the emergence of drug resistance. These results identify Rapa an effective drug to reduce PEL effusions but illustrate the rapid development of drug resistance, which likely limits the efficacy of Rapa in PEL.

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Acknowledgements

Supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. PG supported in part by FIRC (Italian Foundation for Cancer Research). We thank Drs S Steinberg, K Ueda, R Yarchoan, S Pittaluga, D Whitby, S Sakakibara, M Segarra and P McCormick for help on aspects of this work.

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  1. Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    P Gasperini & G Tosato

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Correspondence to P Gasperini.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Gasperini, P., Tosato, G. Targeting the mammalian target of Rapamycin to inhibit VEGF and cytokines for the treatment of primary effusion lymphoma. Leukemia 23, 1867–1874 (2009). https://doi.org/10.1038/leu.2009.117

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