Mulligan Michael P, Boudreau Matthew W, Bouwens Brooke A, Lee Yoongyeong, Carrell Hunter W, Zhu Junyao, Mousses Spyro, Shapiro David J, Nelson Erik R, Fan Timothy M, Hergenrother Paul J
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
ACS Cent Sci. 2025 Jan 22;11(2):228-238. doi: 10.1021/acscentsci.4c01628. eCollection 2025 Feb 26.
Patients with estrogen receptor α positive (ERα+) breast cancer typically undergo surgical resection, followed by 5-10 years of treatment with adjuvant endocrine therapy. This prolonged intervention is associated with a host of undesired side effects that reduce patient compliance, and ultimately therapeutic resistance and disease relapse/progression are common. An ideal anticancer therapy would be effective against recurrent and refractory disease with minimal dosing; however, there is little precedent for marked tumor regression with a single dose of a small molecule therapeutic. Herein we report as a small molecule that induces quantitative or near-quantitative regression of tumors in multiple mouse models of breast cancer with a single dose. Importantly, this effect is robust and independent of tumor size with eradication of even very large tumors (500-1500 mm) observed. Mechanistically, these tumor regressions are a consequence of rapid induction of necrotic cell death in the tumor and are immune cell independent. If successfully translated to human cancer patients, the benefits of such an anticancer drug that is effective with a single dose would be significant.
雌激素受体α阳性（ERα+）乳腺癌患者通常先接受手术切除，随后进行5至10年的辅助内分泌治疗。这种长期干预会带来一系列不良副作用，降低患者的依从性，最终导致治疗抵抗，疾病复发/进展也很常见。理想的抗癌疗法应能以最小剂量有效对抗复发性和难治性疾病；然而，单剂量小分子疗法使肿瘤显著消退的先例很少。在此，我们报告一种小分子，它能在多种乳腺癌小鼠模型中通过单剂量诱导肿瘤发生定量或接近定量的消退。重要的是，这种效果很强，且与肿瘤大小无关，即使是非常大的肿瘤（500 - 1500立方毫米）也能被根除。从机制上讲，这些肿瘤消退是肿瘤中坏死性细胞死亡快速诱导的结果，且与免疫细胞无关。如果能成功转化应用于人类癌症患者，这种单剂量有效的抗癌药物将带来巨大益处。
