Inhibition of Transforming Growth Factor β Signaling Reduces Pancreatic Adenocarcinoma Growth and Invasiveness

Abstract

Transforming growth factor ␤ (TGF␤) is a pleiotropic factor that regulates cell proliferation, angiogenesis, metastasis, and immune suppression. Dysregulation of the TGF␤ pathway in tumor cells often leads to resistance to the antiproliferative effects of TGF␤ while supporting other cellular processes that promote tumor invasiveness and growth. In the present study, SD-208, a 2,4-disubstituted pteridine, ATP-competitive inhibitor of the TGF␤ receptor I kinase (TGF␤RI), was used to inhibit cellular activities and tumor progression of PANC-1, a human pancreatic tumor line. SD-208 blocked TGF␤-dependent Smad2 phosphorylation and expression of TGF␤-inducible proteins in cell culture. cDNA microarray analysis and functional gene clustering identified groups of TGF␤-regulated genes involved in metastasis, angiogenesis, cell proliferation, survival, and apoptosis. These gene responses were inhibited by SD-208. Using a Boyden chamber motility assay, we demonstrated that SD-208 inhibited TGF␤-stimulated invasion in vitro. An orthotopic xenograft mouse model revealed that SD-208 reduced primary tumor growth and decreased the incidence of metastasis in vivo. Our findings suggest mechanisms through which TGF␤ signaling may promote tumor progression in pancreatic adenocarcinoma. Moreover, they suggest that inhibition of TGF␤RI with a small-molecule inhibitor may be effective as a therapeutic approach to treat human pancreatic cancer.

SIX1 Promotes Tumor Lymphangiogenesis by Coordinating TGFβ Signals That Increase Expression of VEGF-C

“…Although the precise relationship between TGFb and tumor lymphangiogenesis is not well known, recent studies suggest that TGFb1 might exert dual effects on lymphangiogenesis. TGFb1 might upregulate VEGF-C expression in some types of cells, including tumor cells (13,14), implying that TGFb1 might contribute to tumor lymphangiogenesis. Conversely, TGFb1 has been found to downregulate VEGF receptor-3 (VEGFR3) in LECs and suppress LEC properties, thus inhibiting lymphangiogenesis (15,16).…”

Inhibition of the TGF-β receptor I kinase promotes hematopoiesis in MDS

“…TBRI selectively participates in TGF-␤ signaling, whereas other activin-like and TGF-␤ receptors can also participate in BMP and activin ligand signaling 49,58 and thus provide selective therapeutic efficacy. SD-208 is a selective 2,4-disubstituted pteridinederived TGF-␤RI kinase inhibitor [23][24][25][26][27][28] that has demonstrated specificity for this kinase. In addition, other TBRI inhibitors are in development 27,59 for various other indications such as chronic renal diseases.…”

“…TBRI inhibitor SD-208 was provided by Scios (Fremont, CA). SD-208 is a selective 2,4-disubstituted pteridine-derived TGF-␤ receptor I (TGF-␤I) kinase inhibitor [23][24][25][26][27][28] that exhibits an in vitro specificity for TGF-␤RI kinase of more than 100-fold compared with TGF-␤RII kinase and at least 20-fold more than members of a panel of related protein kinases. SD-208 was diluted in dimethyl sulfoxide (DMSO; 20 mM stock solution) and kept at Ϫ20°C until use.…”

Therapeutic Efficacy of Bifunctional siRNA Combining TGF-β1 Silencing with RIG-I Activation in Pancreatic Cancer

“…Thus, TGF-b has generated interest as a target for novel anticancer agents. Anti-TGF-b compounds have shown efficacy in preclinical studies, and some of these have moved into clinical investigation for melanoma, brain tumors, colorectal, renal, and pancreatic cancer (7)(8)(9)(10)(11).…”