The TGF-beta1 antisense oligonucleotide AP 11014 for the treatment of non-small cell lung, colorectal and prostate cancer: Preclinical studies

Abstract

3132 Background: Tumor derived transforming growth factor beta (TGF-β) is a pivotal factor for malignant progression by inducing metastasis, angiogenesis and tumor cell proliferation and by mediating the tumors' escape from immunosurveillance. In colorectal, non-small cell lung and prostate cancer in particular expression of the TGF-β1 isoform has been correlated with tumor progression and poor clinical prognosis. Significantly elevated TGF-β1 plasma levels to more than 3fold in colon cancer (median control: 6,200 pg/ml, range: 1,977 - 17,515 pg/ml; median patients: 19,948 pg/ml, range: 5,014 - 38,900 pg/ml) and NSCLC (median control: 3,482 pg/ml, range: 747 - 9,984 pg/ml; median patients: 11,572 pg/ml, range: 4,952 - 30,985 pg/ml) and to more than 4fold in prostate cancer (median control: 2,152 pg/ml, range: 1,275 - 3,958 pg/ml; median patients: 10,066 pg/ml, range: 3,435 - 41,574 pg/ml) further support the role of TGF-β1 as a key tumor promoter. Methods: The in vitro effects of AP 11014, a TGF-β1 specific phosphorothioate antisense oligonucleotide, on TGF-β1 secretion, proliferation, migration of and immunosuppression by various cancer cell lines were determined. Results: AP 11014 significantly reduced TGF-β1 secretion by 43 - 100% in different NSCLC (A549, NCI-H661, SW 900), colon cancer (HCT-116) and prostate cancer (DU-145, PC-3) cell lines. Tumor cell proliferation was inhibited in a dose-dependent manner in all cell lines. In a scratch assay AP 11014 reduced migration of a NSCLC (SW 900) and prostate cancer (PC-3) cell line by max. 65% after 24h. Additionally, AP 11014 reversed immunosuppression mediated by NSCLC (NCI-H661, A-549) and colon cancer (HCT-116) cell derived TGF-β1 by increasing LAK cell cytotoxicity up to 368% of the untreated control (effector/target ratio 5:1). Conclusion: These preclinical data clearly indicate antisense mediated suppression of TGF-β1 by AP 11014 as a highly promising approach for the therapy of non-small cell lung, colorectal and prostate cancer in humans. Based on these data a clinical trial with AP 11014 in TGF-β1 overexpressing tumors is planned. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Antisense Pharma GmbH Antisense Pharma GmbH