Abstract 1220: Selective and broad anti-tumor activity of AKR1C3-activated prodrug AST-3424/OBI-3424

Autor: Tianyang Qi, Donald Jung, Yin-Cheng Hsieh, Ren-Yu Hsu, Jian-Xin Duan, Wan-Fen Li, Chun-Chung Wang, Fanying Meng, Chi-Sheng Shia
Rok vydání: 2021
Předmět:
Zdroj: Cancer Research. 81:1220-1220
ISSN: 1538-7445
0008-5472
Popis: AKR1C3 is overexpressed at both levels of protein and RNA in many types of cancer, particularly in liver, gastric, renal, CRPC and non-small cell lung cancer. High AKR1C3 expression is directly related to treatment resistance and poor prognosis. AST-3424/OBI-3424 (denoted by 3424) is a novel prodrug activated by AKR1C3. Currently 3424 is being studied in phase I clinical trials for the treatment of solid and hematologic cancers. Here we characterize 3424 on its specificity against AKR1C3 in biochemical and cell-based assays. In addition, its anti-tumor activity as a single agent or in combination therapy in a broad panel of CDX and PDX models was also investigated. AKR1C3-dependent activation of prodrug 3424 was evident by monitoring the decrease of 3424 and generation of the active form, 2660, based on LC/MS-MS analysis. Kinetic analysis indicated that AKR1C3 exhibited higher catalytic efficiency towards 3424 compared to the physiological substrates. Cytotoxicity of 3424 was found to be dependent on the level of AKR1C3 expression in a wide range of human cancer cell lines. There was a strong correlation between 3424 cytotoxic potency and AKR1C3 expression at both protein and RNA levels across all the cell lines examined. Cytotoxicity of 3424, its enantiomer and racemic mixture were also greatly inhibited by the AKR1C3-specific inhibitor 3021. The racemic mixture induced DNA cross-linking in a concentration dependent manner. Tumor growth inhibition of 3424 was shown to be better than or comparable to the standard of care chemotherapy at clinically achievable doses as a single agent in various CDX models with high expression of AKR1C3 at both levels of protein and RNA, including gastric SNU-16, kidney A498, and castration-resistant prostate VCaP, liver HepG2 and lung H460 cancers. The excellent anti-tumor efficacy of 3424 was further demonstrated in PDX models that have high level of AKR1C3 expression (pancreatic PA1280, gastric GA6201, Lung cancer LU2505) but not in model with low level of AKR1C3 expression (lung cancer LU2057). A significant correlation was found between AKR1C3 expression level and 3424 anti-tumor activity in two lung LU2505 and LU2057 PDX xenograft models confirming that 3424 in vivo activity is AKR1C3-dependent, which is consistent with its AKR1C3-dependent cytotoxicity in vitro. In the combination therapy, we have showed that 3424 could enhance the efficacy of the standard care of chemotherapy in the CDX models of VCaP CRPC, SNU-16 gastric, and A498 renal cell carcinoma. In conclusion, the results described here highlight that 3424 exhibits AKR1C3-dependent cytotoxicity in vitro and anti-tumor activity in vivo in a wide range of human cancer types, which support further development of 3424 as an anti-cancer agent for treating different types of cancer and the use of AKR1C3 as a biomarker to profile cancer patients and further guide patient selection for therapy with 3424. Citation Format: Fanying Meng, Wan-Fen Li, Donald Jung, Chun-Chung Wang, Tianyang Qi, Chi-Sheng Shia, Ren-Yu Hsu, Yin-Cheng Hsieh, Jianxin Duan. Selective and broad anti-tumor activity of AKR1C3-activated prodrug AST-3424/OBI-3424 [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 1220.
Databáze: OpenAIRE
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