TGF-β2 suppression by the antisense oligonucleotide AP 12009 as treatment for pancreatic cancer: preclinical efficacy data

Abstract

4106 Background: With a 5-year-survival rate of less than 1% pancreatic cancer is one of the most aggressive human cancers. Overexpression of TGF-beta2 in malignancies correlates with decreased survival and is associated with advanced tumor stage due to its pivotal role in malignant progression by inducing key mechanisms including immunosuppression, metastasis, angiogenesis and tumor cell proliferation. In pancreatic cancer patients TGF-beta2 levels were significanty elevated (median: 1,198 pg/ml; range: 319–1,713 pg/ml) as compared to healthy controls (median: 378 pg/ml; range: 241–575 pg/ml). Methods: Aiming at a highly specific anti-tumor therapy, AP 12009, a phosphorothioate antisense oligonucleotide specific for the human TGF-beta2 mRNA, has been developed and tested for its anti-tumor activity in a variety of preclinical studies with pancreatic cancer cells. Results: AP 12009 significantly reduced the TGF-beta2 secretion in several human pancreatic cancer cell lines (Hup-T3, Hup-T4, PA-TU 8902). In functional assays AP 12009 inhibited pancreatic tumor cell proliferation in a dose-dependent manner by up to 76%. Migration of PA-TU 8902 cells was completely blocked as compared to untreated controls in a spheroid migration model while TGF-beta2 antibody had no effect. Additionally, AP 12009 reversed TGF-beta2 mediated immunosuppression in an allogenic PA-TU 8902 system targeted by IL-2 activated PBMC (LAK cells) derived from healthy donors. After AP 12009 treatment LAK cell cytotoxicity was increased in a donor-dependent manner up to 708% of the untreated control (effector/target ratio 20:1). Conclusions: AP 12009 has already shown efficacy in phase I/II clinical studies as therapy for high-grade glioma. Based on this successful application of AP 12009 in clinical studies and the presented preclinical efficacy in tumor proliferation, migration and inhibition of escape from immunosurveillance in pancreatic cancer a multi-site dose-escalation trial with AP 12009 in pancreatic carcinoma is currently being initiated. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Antisense Pharma