Abstract 2951: Potent antisense pharmacology of highly optimized antisense oligonucleotides in multiple transgenic, spontaneous and patient derived xenograft models of cancer reveals antitumor activity for the non-coding RNA MALAT-1.

Antisense technology holds great promise as a novel drug discovery platform that can rapidly translate discoveries from cancer genomics into highly selective therapeutics. Antisense oligonucleotices (ASOs) are particularly attractive, as they can be applied to difficult to drug target classes currently not tractable by other therapeutic modalities. Recent clinical demonstration of activity for ASOs in cancer patients supports the potential of this drug class, however, challenges in demonstrating robust antisense pharmacology in preclinical cancer models has slowed the progress of this technology as cancer therapeutics. Here we have employed a high resolution in-situ hybridization-based methodology (QuantigeneTM) among other detection methods, to demonstrate visually and quantitatively the activity of systemically administered, high potency next generation antisense oligonucleotides, in multiple preclinical cancer models. Cancer models evaluated include, transgenic models, chemically induced tumor, genetically predisposed mouse strains, cell line derived xenograft and patient derived xenograft models. As a test antisense target RNA sequence we chose the non-coding RNA MALAT1 (also called NEAT2) because it is ubiquitously expressed at high levels in most cell types and thus RNA levels could be readily visualize at the cellular level by Quantigene method. In addition, as MALAT-1 is overexpressed in many human tumors it also had the potential to be a therapeutically relevant target. We screened >1000 ASO sequences in vitro and identified highly potent mouse and mouse/human cross reactive MALAT-1 ASOs that reduced target RNA in cells in culture with IC50 values in the low nanomalor range (10-50 nM), without any lipid mediated delivery vehicles (ASO free uptake). Systemic delivery (s.c. administration of ASOs formulated in saline) of MALAT1 ASOs in vivo were well tolerated in all animals tested, and reduced target RNA by 70–>90% in the tumor cells of APC/min- mice, prostate tumor cells of the TRAMP model, DEN-induced HCC tumors as well as in the tumor cells of several human tumor xenograft models and in a patient derived NSCLC primary tumor explants model. Interestingly, MALAT-1 inhibition by ASOs was also associated with significant antitumor effects including inhibition of tumor formation and decreased BrdU positive cells in the polyps of APC/min- mice, decrease tumor growth in TRAMP prostate tumors and DEN HCC tumors and significant tumor growth delays in several xenograft and human tumor explant models. These data demonstrate unequivocal, potent, ASO mediated antisense activity of highly optimized next generation ASOs targeting MALAT-1 by systemic administration and highlight a previously uncharacterized role of the ncRNA MALAT1 as regulator of tumor growth in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2951. doi:1538-7445.AM2012-2951