Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.
Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea; Radiological and Medico-Oncological Sciences, University of Science and Technology, Seoul, South Korea.
Eur J Cancer. 2022 Sep;173:41-51. doi: 10.1016/j.ejca.2022.06.031. Epub 2022 Jul 15.
Tankyrase inhibition stabilises AXINs and antagonises the Wnt/β-catenin pathway in adenomatous polyposis coli (APC)-mutated colorectal cancer (CRC), suggesting that tankyrase is a potential therapeutic target for APC-mutated CRC. However, clinical trials on reported tankyrase inhibitors have been severely limited by on-target toxicity in the gastrointestinal (GI) tract. Herein, we report a new tankyrase-selective inhibitor, STP1002, having preclinical antitumour efficacy without on-target toxicity in APC-mutated CRC models.
STP1002 was developed and characterised using in vitro and in vivo functional studies; its pharmacokinetics, antitumour efficacy and toxicity were evaluated in vivo.
STP1002 showed potent, selective inhibition of tankyrase 1/2 but not of members of the poly (ADP-ribose) polymerase 1/2 (PARP1/2). STP1002 exerted antitumour activity by stabilising AXINs and antagonising the Wnt/β-catenin pathway in a subset of APC-mutated CRC cell lines but not in inhibitor-resistant cells and APC-wild-type CRC cell lines. STP1002 showed favourable pharmacokinetic profiles for oral administration once daily. STP1002 inhibited tumour growth of APC-mutated CRC xenograft animal models but not of APC-wild type models in a dose-dependent manner. The antitumour efficacy of STP1002 was confirmed using APC-mutated CRC patient-derived tumour xenograft models. STP1002 showed no significant on-target toxicity in the GI tract compared to G007-LK, which shows severe ileum toxicity in preclinical animal models.
These results demonstrate that STP1002, a novel, orally active tankyrase inhibitor, shows preclinical antitumour efficacy without on-target toxicity in the GI tract. Our data provide a rationale for a clinical trial on STP1002 as a potential tankyrase-targeted drug in patients with APC-mutated CRC.
在腺瘤性结肠息肉病（APC）突变的结直肠癌（CRC）中，端锚聚合酶抑制稳定 AXIN 并拮抗 Wnt/β-连环蛋白通路，这表明端锚聚合酶是 APC 突变 CRC 的潜在治疗靶点。然而，报告的端锚聚合酶抑制剂的临床试验受到胃肠道（GI）中靶毒性的严重限制。在此，我们报告了一种新型的端锚聚合酶选择性抑制剂 STP1002，它在 APC 突变的 CRC 模型中具有临床前抗肿瘤疗效，而没有靶毒性。
使用体外和体内功能研究开发和表征 STP1002；评估其在体内的药代动力学、抗肿瘤疗效和毒性。
STP1002对端锚聚合酶 1/2 表现出强大的选择性抑制作用，但对聚（ADP-核糖）聚合酶 1/2（PARP1/2）的成员没有抑制作用。STP1002通过稳定 AXINs 和拮抗 Wnt/β-连环蛋白通路在 APC 突变的 CRC 细胞系中发挥抗肿瘤活性，但在抑制剂抗性细胞和 APC 野生型 CRC 细胞系中没有。STP1002具有良好的口服给药药代动力学特征，每天一次。STP1002以剂量依赖性方式抑制 APC 突变的 CRC 异种移植动物模型的肿瘤生长，但不抑制 APC 野生型模型的肿瘤生长。STP1002在 APC 突变的 CRC 患者来源的肿瘤异种移植模型中证实了其抗肿瘤疗效。与在临床前动物模型中显示严重回肠毒性的 G007-LK 相比，STP1002在胃肠道中没有明显的靶毒性。
这些结果表明，新型口服活性端锚聚合酶抑制剂 STP1002 在 APC 突变的 CRC 中具有临床前抗肿瘤疗效，而没有胃肠道中的靶毒性。我们的数据为在 APC 突变的 CRC 患者中进行 STP1002 作为潜在的端锚聚合酶靶向药物的临床试验提供了依据。
