In Vitro And In Vivo Antitumor Activity Of Th3424: Preclinical Rationale For A Highly Selective Akr1c3 Prod Rug For Treating Hepatocellular Carcinomas

Aldo-keto reductase family 1 member C3 (AKR1C3) catalyzes the reduction of a diverse group of substrates, including prostaglandin (PG) D2 and PGH2. It has been reported that AKR1C3 is overexpressed in the majority of hepatocellular carcinomas (HCC) with 58% of HCC patient surgical tumor samples having strong expression of the enzyme 1 . Tumors overexpressing AKR1C3 can be resistant to radiation therapy 2 and chemotherapies 3 . AKR1C3 is also expressed in normal tissues,but its expression is much lower than in HCC tissue 1 . HCC is the sixth most common cause of cancer. It has very poor prognosis, and is the second leading cause of cancer death in all cancers. Treatment options for late stage liver cancer are very limited, with Sorafenib, a multi-tyrosine kinase inhibitor, being the only approved drug with limited efficacy. More effective therapies are urgently needed. TH3424 is a prodrug which selectively releases a DNA alkylating agent upon exposure to activated AKR1C3. In vitro cell proliferation tests with TH3424 in several HCC cell lines showed that it is very potent (IC 50 ≤ 10 nM with 2 hour exposure) in killing cancer cells with high levels of AKR1C3, but less active (IC 50 ≥ 10 μM) in killing cells with low or no AKR1C3 reductase. The activity of TH3424 correlates with the expression level of AKR1C3 as the potency of TH3424 is inhibited when used with a specific AKR1C3 inhibitor: 4 (IC 50 : 4 nM vs 6.3 μM with SN33638) in a non-small cell lung cancer cell line (H460). In vivo orthotopic and patient derived disease (PDX) liver cancer model studies have shown promising efficacy with TH3424 being administer weekly with doses as low as 1.5mg/kg. TH3424 showed better efficacy than Sorafenib in an orthotopic HepG2 mouse model. Three of 8 mice treated with TH3424 at 2.5 mg/kg, Q7Dx3, and 8 of 8 mice treated with TH3424 at 5 mg/kg, Q7Dx3 were tumor free at day 35. Reference:1: Guise C. P.; Abbattista M. R.; Singleton R. S.; Holford S. D.; Connolly J.; Dachs G. U.; Fox S. B.; Rollock R.; Harvey J.; Guiford P.; Daňate F.; Wilson W. R.; and Patterson A. V.; Cancer Res.70(4), 2010, 1573 2: Xiong W.; Zhao J.; Yu H.; Li X.; Sun S.; Li Y.; Xia Q.; Zhang C.; He Q.; Gao X.; Zhang L.; Zhou D.; Plos One, V. 9 (11), 2014, e111911 3: Liu C.; Lou W.; Zhu Y.; Yang J.; Nadiminty N.; Gaikwad N.; Evans C.; Gao A.; Cancer Res.; 2015, 75(7), 1413 4: Flanagan J. U.; Atwell G. J.; Heinrich D. M.; Brooke D. G.; Silva S.; Rigoreau L. J. M.; Trivier E.; Turnbull A. P.; Raynham T.; Jamieson S. M. F.; Denny W. A.; Bioorg. Med. Chem.; 22(2014); 967 Citation Format: Jianxin Duan, Zhong Wang, Qing Li, Yeyu Cao, Ping He, Fanying Meng, Changhua Zhou, Yanhong Wang, Gavin Qu, Henry Li, Jiang Li, Meng Yang, Hui Qi, Don Jung, Mei Song, Mark Matteucci. In vitro and in vivo antitumor activity of TH3424: Preclinical rationale for a highly selective AKR1C3 prodrug for treating hepatocellular carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1369.