Recent evidence supports a strong role for immune suppression in facilitating cancer progression. Transforming growth factor beta (TGFß) regulates a diverse array of biological events, including neoangiogenesis, stromal formation, and immune responses. Both TGFß and a small molecule inhibitor of TGFßR-1, LY364947, were effective regulators of these processes in vitro. Using quantitative RT-PCR and fluorescence imaging, TGFß increased collagen production by pancreatic stellate cells while addition of LY364947 suppressed production below basal levels. Endothelial cell proliferation, measured as a function of endothelial tube formation in Geltrex® matrix, was similarly increased by TGFß and reduced to basal levels by LY364947. To explore the in vivo effects of these molecules, LY364947 was encapsulated in liposomes to encourage tumor accumulation and to avoid administration of DMSO vehicle. Liposomes were prepared with a molar ratio of 6:3:1 1,2-dipalmitoyl-sn-glycero-3-phosphocholine /Chol/1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] using a Hei-Vap Series Heidolph Rotatory Evaporator and a Thermobarrel Extruder. In contrast to in vitro studies, tumor stromal content in human pancreatic capan-2 tumors established in nude mice was not influenced by LY364947, free or liposomal. In addition, tumor progression, as a function of size, and myeloid populations were unaltered by weekly treatments with liposomal LY364947. Thus the influence of TGFßR-1 inhibition in cell cultures does not translate directly into biologically equivalent events.
Citation Format: Ismail Meraz, Leoncio Vergara, Sarah Suki, Prem Siddharth Gunamalai, Rita Elena Serda. Transforming growth factor-beta as a therapeutic target for pancreatic cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A118.