trabedersen and Pancreatic-Neoplasms

Despite the enormous advances in clinical research in oncology, the prognosis of pancreatic carcinoma remains poor. The therapeutic options in this type of cancer are very limited, with modest results at present. In the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, four interesting trials on the second line treatment of pancreatic cancer were presented. The first study (Abstract #4017) with a phase II design suggested that maintenance therapy with sunitinib, after a complete course of standard first line treatment, was feasible and effective while the second phase I/II study (Abstract #4034) evaluated the role of trabedersen, an agent that inhibits TGF-β2 expression. Finally, the efficacy and toxicity of lapatinib combined with either FOLFOX (Abstract #e14533) or capecitabine (Abstract #e14569) were examined in the second line setting of pancreatic cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Clinical Trials as Topic; Deoxycytidine; Fluorouracil; Humans; Lapatinib; Leucovorin; Oligodeoxyribonucleotides; Organoplatinum Compounds; Pancreatic Neoplasms; Quinazolines; Thionucleotides

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-β2) 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-β2 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-β2 secretion in human pancreatic cell lines with an IC50 in the low μM range without transfection reagent, clearly inhibited cell proliferation, and completely blocked migration of pancreatic cancer cells. Additionally, trabedersen reversed TGF-β2-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.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Silencing; Humans; Inhibitory Concentration 50; Killer Cells, Lymphokine-Activated; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Oligodeoxyribonucleotides; Pancreatic Neoplasms; Thionucleotides; Transforming Growth Factor beta2; Xenograft Model Antitumor Assays