Abstract 4786: BP1003, a novel liposome-incorporated STAT3 antisense oligodeoxynucleotide inhibitor
Authors: Dai Bingbing , Ashizawa Ana Tari , Augustine Jithesh J. , Kim Michael , Fleming Jason 
Published: August 2019

Abstract
Background: Signal Transduction and Activator of Transcription-3 (STAT3), though typically inactive in normal cells, is aberrantly active in cancer cells. Activation of STAT3 has been found in many types of cancers, including non-small cell lung cancer (NSCLC), acute myelogenous leukemia (AML), and pancreatic ductal adenocarcinoma (PDAC). Activation of STAT3 correlates with poor clinical outcome, high grade disease and metastasis, and has been linked with resistance to chemotherapy, including gemcitabine, which is one of the standard of care agents for advanced PDAC. Therefore, inhibition of STAT3 in combination with chemotherapy is expected to produce clinical benefit. We have developed BP1003, a novel liposome-incorporated STAT3 antisense oligodeoxynucleotide (oligo) as a specific inhibitor of STAT3.
Methods: Four candidate antisense oligo sequences directed against STAT3 mRNA were initially identified. They were manufactured as nuclease-resistant P-ethoxy oligos and incorporated into neutral dioleoylphosphatidylcholine liposomes. Cell viability tests and Western blots were conducted to determine the inhibitory effects of liposome-incorporated STAT3 antisense oligo on NSCLC and AML cells. Ex vivo live tissue sensitivity assay (LTSA) was performed with a panel of 20 PDAC patients-derived xenografts (PDXs) to study the overall activity of BP1003, alone and in combination with gemcitabine. Using previous defined criteria, tissue slice viability inhibition greater than 30% and p&lt;0.05 was considered to be a response. For validation of ex vivo results, PDAC PDX tumor bearing mice were administered with BP1003 and gemcitabine twice a week for 28 days. Tumor volumes were monitored for up to 49 days.
Results: The most potent liposome-incorporated STAT3 antisense sequence in decreasing NSCLC cell viability was selected as the candidate BP1003 drug. Further validation in AML cells demonstrated that BP1003 inhibited cell viability and STAT3 protein expression. In the ex vivo LTSA assay, BP1003, at a dose of 10 µM, significantly inhibited the tissue slice viability of 9 out of 18 PDAC PDXs by over 30% (p&lt;0.05). Combination of BP1003 and gemcitabine further enhanced ex vivo efficacy of BP1003 in a subset of PDXs. In the in vivo study with PDAC PDX models, combination of BP1003 and gemcitabine caused tumor regression during the 28-day drug treatment period. This anti-cancer activity was maintained for another 21 days, even when drug treatment had ceased.
Conclusions: Liposome-incorporated STAT3 antisense oligo, BP1003, shows promising in vitro and in vivo preclinical activity as single and combination agent and might be a novel therapeutic strategy in patients with advanced tumors and/or metastasis.
Citation Format: Bingbing Dai, Ana Tari Ashizawa, Jithesh J. Augustine, Michael Kim, Jason Fleming. BP1003, a novel liposome-incorporated STAT3 antisense oligodeoxynucleotide inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4786.