Abstract 1152: Targeted inhibition of SIRT6 by engineered exosomes suppressed tumorigenesis and metastasis in prostate cancer
Authors: Han Qing , Xie Qian Reuben , Li Fan , Cheng Yirui , Wu Tingyu , Sha Jianjun , Xia Weiliang 
Published: July 2021

Abstract
The great majority of prostate cancer occurrence and development are driven by androgen receptor signaling, which has led to androgen dependent therapy (ADT) as the backbone of systemic therapy for advanced prostate cancer patients until now. Although ADT has improved clinical outcome in patients with castration-sensitive disease and the next-generation androgen receptor pathway inhibitors (ARPIs) like enzalutamide are commonly used in advanced prostate cancer patients, the cross-resistance between AR-targeted drugs significantly limits the therapeutic effect. Besides, early use and potentially long exposure to ARPIs preferentially lead to the evolvement of the alternative downstream signaling instead of AR pathway. Hence, targeting the AR fails to develop inescapable drug resistance, and no effective approach is available for targeting metastatic and castration-resistant prostate cancer (mCRPC), which is a major clinical challenge in prostate cancer treatment. Undoubtedly, new targets and therapeutic strategies are needed to improve the clinical outcomes.
Sirt6 belongs to the Sirtuin family proteins, and as a nuclear protein, regulates diverse physiological functions like aging and metabolism. Silencing SIRT6 could inhibit prostate cancer proliferation, and in this study, we further exploited this phenomenon. We found that expression of SIRT6 was positively related with the Gleason score of the patients' prostate tissue sample and knockdown the expression of SIRT6 in prostate cancer cell lines significantly reduced migration and invasion both in vitro and in vivo. Furthermore, SIRT6 deficiency upregulated the expression of E-cadherin and downregulated the expression of N-cadherin and Vimentin, suggesting its role in regulation of epithelial-mesenchymal transition (EMT). Silencing SIRT6 inhibited both the proliferation and metastasis in prostate cancer, indicating the therapeutic value of targeting SIRT6 in the treatment of metastatic PCa. We then tested the therapeutic value of SIRT6 in prostate cancer in vivo by using aptamer-modified exosomes carrying SIRT6 siRNA. To achieve this goal, the cholesterol-covalent E3 aptamer was inserted into the membrane of 293T-derived exosomes to target specifically the prostate cancer cells, followed by SIRT6-siRNA loading into the modified exosomes with an electroporation apparatus. The engineered exosomes suppressed the proliferation and metastasis in subcutaneously and orthotopically xenograft mice tumor models, and confirmed that SIRT6 could be considered as a selective and novel target in high-grade prostate cancer.
Citation Format: Qing Han, Qian Reuben Xie, Fan Li, Yirui Cheng, Tingyu Wu, Jianjun Sha, Weiliang Xia. Targeted inhibition of SIRT6 by engineered exosomes suppressed tumorigenesis and metastasis in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1152.