Department of Pharmacology and Toxicology, Michigan State University College of Osteopathic Medicine, B430 Life Science Building, 1355 Bogue Street, East Lansing, MI, 48824, USA.
School of Mathematical and Natural Sciences, New College of Interdisciplinary Arts and Sciences, Arizona State University, Glendale, AZ, USA.
Sci Rep. 2022 Jan 7;12(1):293. doi: 10.1038/s41598-021-04415-0.
Rexinoids are ligands which activate retinoid X receptors (RXRs), regulating transcription of genes involved in cancer-relevant processes. Rexinoids have anti-neoplastic activity in multiple preclinical studies. Bexarotene, used to treat cutaneous T cell lymphoma, is the only FDA-approved rexinoid. Bexarotene has also been evaluated in clinical trials for lung and metastatic breast cancer, wherein subsets of patients responded despite advanced disease. By modifying structures of known rexinoids, we can improve potency and toxicity. We previously screened a series of novel rexinoids and selected V-125 as the lead based on performance in optimized in vitro assays. To validate our screening paradigm, we tested V-125 in clinically relevant mouse models of breast and lung cancer. V-125 significantly (p < 0.001) increased time to tumor development in the MMTV-Neu breast cancer model. Treatment of established mammary tumors with V-125 significantly (p < 0.05) increased overall survival. In the A/J lung cancer model, V-125 significantly (p < 0.01) decreased number, size, and burden of lung tumors. Although bexarotene elevated triglycerides and cholesterol in these models, V-125 demonstrated an improved safety profile. These studies provide evidence that our screening paradigm predicts novel rexinoid efficacy and suggest that V-125 could be developed into a new cancer therapeutic.
类视黄醇是激活视黄醇 X 受体 (RXR) 的配体，可调节与癌症相关过程的基因转录。在多项临床前研究中，类视黄醇具有抗肿瘤活性。贝沙罗汀用于治疗皮肤 T 细胞淋巴瘤，是唯一获得 FDA 批准的类视黄醇。贝沙罗汀也已在肺癌和转移性乳腺癌的临床试验中进行了评估，尽管疾病处于晚期，但部分患者有反应。通过修饰已知类视黄醇的结构，我们可以提高其效力和毒性。我们之前筛选了一系列新型类视黄醇，并根据优化的体外测定结果选择 V-125 作为先导化合物。为了验证我们的筛选模式，我们在乳腺癌和肺癌的临床相关小鼠模型中测试了 V-125。V-125 显著（p<0.001）延迟了 MMTV-Neu 乳腺癌模型中肿瘤的发展时间。用 V-125 治疗已建立的乳腺肿瘤显著（p<0.05）增加了总生存期。在 A/J 肺癌模型中，V-125 显著（p<0.01）减少了肺肿瘤的数量、大小和负担。尽管贝沙罗汀在这些模型中升高了甘油三酯和胆固醇，但 V-125 表现出改善的安全性。这些研究为我们的筛选模式预测新型类视黄醇疗效提供了证据，并表明 V-125 可能开发成为一种新的癌症治疗药物。
