Details

Autor(en) / Beteiligte

• Fesler, Andrew
• Hwang, Ga-Ram
• Yuen, John
• Ju, Jingfang

Titel

Abstract 4063: Design and development of a novel 5-FU modified siRNA against BCL2 with enhanced efficacy and the unique ability to be delivered vehicle free into cancer cells

Ist Teil von

• Cancer research (Chicago, Ill.), 2020-08, Vol.80 (16_Supplement), p.4063-4063

Erscheinungsjahr

2020

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Abstract Evasion of apoptosis is one of the major hallmarks of cancer and an important factor in chemoresistance. Thus, targeting apoptosis regulation is an important therapeutic approach. Anti-apoptotic BCL2, an oncogene and therapeutic target, is overexpressed in several different cancer types. There have been various approaches developed to target BCL2 including the FDA approved Venetoclax. In this study we have developed a modified siRNA against BCL2 that has enhanced efficacy and also can be delivered into cancer cells without any vehicle. We developed this siRNA by replacing uracil residues in the siRNA with 5-flurouracil (5-FU). This modification incorporates the effects of both 5-FU and siBCL2, to have an enhanced therapeutic effect. We tested several different modified siBCL2's, one with only the sense strand modified, one with only the antisense strand modified and one with both strands modified. We found the modified siBCL2 with both strands modified with 5-FU was most effective at inhibiting BCL2. Importantly, we were able to demonstrate via qRT-PCR and Western blot, that this modified siBCL2 retains its siRNA function and inhibits BCL2 expression in several different cancer types including colon cancer, lung cancer and lymphoma. In addition, in lymphoma cells, we found that our modified siBCL2 has better efficacy than BCL2 inhibitor Venetoclax. Finally, we were able to demonstrate that modified siBCL2 can be delivered into cancer cells without a delivery vehicle. This unique feature may be significant in overcoming the challenge of delivery, which remains a major obstacle for RNA therapeutics. This modified siBCL2 has therapeutic potential for several different cancers. Beyond BCL2, the modification approach we demonstrated may be applicable to other siRNAs and has potential as a platform technology for siRNA based therapeutics. Citation Format: Andrew Fesler, Ga-Ram Hwang, John Yuen, Jingfang Ju. Design and development of a novel 5-FU modified siRNA against BCL2 with enhanced efficacy and the unique ability to be delivered vehicle free into cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4063.