Transforming growth factor‐beta 2 gene silencing with trabedersen (AP 12009) in pancreatic cancer

Abstract

Pancreatic cancer is one of the most aggressive human cancers with a 5-year survival rate of <5%. Overexpression of transforming growth factor-beta 2 (TGF-b2) in pancreatic malignancies is suggested to be a pivotal factor for malignant progression by inducing immunosuppression, metastasis, angiogenesis and proliferation. Trabedersen (AP 12009) is a phosphorothioate antisense oligodeoxynucleotide specific for human TGF-b2 mRNA and was successfully tested in a randomized, active-controlled phase IIb clinical study in patients with high-grade glioma. Here, we report on the antitumor activity of trabedersen in human pancreatic cancer cells and in an orthotopic xenograft mouse model of human metastatic pancreatic cancer. Trabedersen reduced TGF-b2 secretion in human pancreatic cell lines with an IC 50 in the low lM range without transfection reagent, clearly inhibited cell proliferation, and completely blocked migration of pancreatic cancer cells. Additionally, trabedersen reversed TGF-b2-mediated immunosuppression of pancreatic cancer cells targeted by lymphokine activated killer (LAK) cells, resulting in considerably increased LAK cell-mediated cytotoxicity. Moreover, in an orthotopic mouse model of metastatic pancreatic cancer, intraperitoneal (i.p.) treatment with trabedersen significantly reduced tumor growth, lymph node metastasis and angiogenesis. These promising results warrant further clinical development of trabedersen. (Cancer Sci 2011; 102: 1193-1200

Targeting TGF-β Signaling for Therapeutic Gain

“…2; Table 1), including a pyrrole-imidazole polyamide drug that blocks transcription of the TGFB1 target gene (Yao et al 2009;Chen et al 2010;Matsuda et al 2011;Washio et al 2011;Igarashi et al 2015), antisense RNAs that target TGFB1 or TGFB2 mRNAs for degradation (Hau et al 2009;Vallieres 2009;Schlingensiepen et al 2011), antibodies against TGF-b ligands or receptors that block ligand -receptor engagement, and many small molecule ATP-mimetic TbRI kinase inhibitors (Fig. 2).…”

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).…”

Fetal bovine serum (FBS): Past – present – future

“…For most of the commonly used cell lines, cultivation of the cells only becomes challenging if the final concentration of FBS is lower than 1% (in combination with additional chemically-defined serum-free replacements). At this low concentration, the culture medium has become notably defined, while the reproducibility of the experiments can be improved significantly (Schlingensiepen et al, 2011). However, the examples presented here demonstrate that it is possible to obtain reliable results in serum-free cell and complex organ systems.…”