08 May Gene-silencing RNAs Targeting CTNNB1 and PD-L1 May Attack a Variety of Cancers
MedicalResearch.com Interview with:
Dr. Youzhi Li
Vice President at Boston Biomedical
MedicalResearch.com: What are the main findings?
Response: RNAi (RNA interference) technology has the potential to target any genes causing disease, including conventionally “undruggable” targets in cancer. One particularly interesting RNAi target in oncology is the CTNNBI oncogene, which encodes the β-Catenin protein whose nuclear form acts as a transcription factor promoting tumorigenesis. Aberrant β-Catenin signaling has been demonstrated in 90 percent of colorectal carcinomas, 40 percent of hepatocellular carcinoma, and 90 percent of non-ductal pancreatic carcinomas. Recent research also suggests active β-Catenin contributes to tumor immune evasion and to the recurrence of melanoma in patients post the check-point blockage immunotherapy.
However, the direct blockade of β-Catenin activity has proved difficult with conventional approaches. While the application of traditional RNAi technology has the potential to block this pathway, in clinical cancer therapy, this approach has proven challenging due to the difficulty in systemic delivery of RNAi to tumor sites located in various organs.
We have recently developed BBI-801, a lipid-based nanoparticle that encapsulates therapeutic aiRNAs targeting CTNNB1 and PD-L1 to simultaneously target immune evasion via both these pathways. Here, we investigate the in vivo delivery and anti-tumor activity of BBI-801.
MedicalResearch.com: What are the main findings?
Response: In our in vivo studies, we have achieved prolonged silencing of β-Catenin and PD-L1 mRNA and protein in a wide variety of murine tumor models, including subcutaneous human tumor xenografts, orthotopic human liver and pancreatic tumors, as well as syngeneic mouse colorectal, breast and lung tumors. Our biodistribution analysis of fluorescence-labeled aiRNA demonstrated that the delivery of BBI-801 to xenograft tumors happens within five minutes of aiRNA administration and lasts at least eight hours. Finally, BBI-801 is well-tolerated and no signs of toxicity were observed after repeated dosing.
MedicalResearch.com: What should readers take away from your report?
Response: BBI-801, the combination of aiRNAs targeting β-Catenin and PD-L1 in a lipid-based nanoparticle formulation, and may provide a potential treatment for diverse tumor types located in different organs.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: These data support further investigation of the anti-tumor potential of BBI-801 as an anti-cancer therapeutic in variety of tumor indications. Furthermore the aiRNA technology can be applied to other undruggable oncology targets.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
Citation: AACR April 2017 Interview
In vivo delivery of asymmetric gene-silencing RNAs targeting CTNNB1 and PD-L1 show a broad spectrum of potent antitumor activities in preclinical cancer models
Youzhi Li, Yuan Gao, Yuxin Wang, Jie Su, Eric Hsu, Ewa Wybieralska, Janet Huang, Keyur Gada, Jun Oishi, Xiaoshu Dai, Erina Koga, Wei Li, Xiangao Sun, Emily Brooks, Chiang J. Li.; Boston Biomedical Inc., Cambridge, MA
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Last Updated on May 9, 2017 by Marie Benz MD FAAD