Abstract 3849: Mast cell inhibition by Btk inhibitor PCI-32765 as a potential cancer therapy

Abstract

An association between inflammation and cancer has long been recognized but the cause and effect relationship linking the two remains unclear. Myc is a pleiotropic transcription factor that is over-expressed in many human cancers and instructs multiple extracellular aspects of the tumor tissue phenotype, including remodeling of tumor stroma and angiogenesis. We have shown in a

β cell tumor model that Myc activation in vivo triggers rapid recruitment of mast cells to the tumor site, a recruitment that is absolutely required for macroscopic tumor expansion. Indeed, such tumors did not grow in mast cell deficient mice. Furthermore, treatment of established β cell tumors with cromolyn, a stabilizer that prevents mast cell degranulation, rapidly triggered hypoxia and cell death of tumor and endothelial cells. Inhibitors of mast cell function may therefore prove therapeutically useful in restraining expansion and survival of pancreatic cancer. However, such compounds have not yet been developed for systemic administration and applications in cancer therapy. In fact, there are no clinically effective mast-cell blockers. Therefore, we tested PCI-32765 (Pharmacyclics, Inc.), a Bruton's tyrosine kinase (BTK) inhibitor in clinical trials for B cell non-Hodgkin's lymphoma, for its ability to inhibit mast cell function and tumorigenesis in our mouse model of β cell neoplasia. Here we show that long term treatment with PCI-32765 prevents mast cell degranulation and causes tumor regression and vasculature collapse. Surprisingly, the compound also displays an unexpected anti-proliferative effect on tumor cells - but not surrounding normal tissue - which is still under investigation. Our results once more support the idea that mast cell inhibition could be beneficial in the treatment of insulinomas and possibly other pancreatic cancers and suggests that PCI-32765 could open the way to clinical studies assessing this potential.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3849.