Department of Radiology, Canary Center at Stanford for Cancer Early Detection, Stanford University, Palo Alto, California.
Mol Cancer Ther. 2019 Jul;18(7):1230-1242. doi: 10.1158/1535-7163.MCT-18-0804. Epub 2019 Apr 26.
Prostate cancer remains among the leading causes of cancer-related deaths in men. Patients with aggressive disease typically undergo hormone deprivation therapy. Although treatment is initially very successful, these men commonly progress to lethal, castration-resistant prostate cancer (CRPC) in 2 to 3 years. Standard therapies for CRPC include second-generation antiandrogens, which prolong patient lifespan by only several months. It is imperative to advance our understanding of the mechanisms leading to resistance to identify new therapies for aggressive prostate cancer. This study identifies Notch1 as a therapeutic target in prostate cancer. Loss of in aggressive prostate cancer cells decreases proliferation, invasion, and tumorsphere formation. Therapeutic inhibition of Notch1 activity with gamma secretase inhibitors RO4929097 or DAPT in prostate cancer cells further results in decreased proliferative abilities. Loss of and treatment of immunocompromised mice bearing prostate cancer xenografts with RO4929097 display significantly impaired tumor growth. Loss of additionally decreased metastatic potential of prostate cancer cells in invasion assays as well as experiments. Moreover, treatment with gamma secretase inhibitors or gene deletion synergized with antiandrogen therapies, enzalutamide or abiraterone, to decrease the growth of prostate cancer cells. Combination of gamma secretase inhibitors with abiraterone significantly inhibited cell migration and invasion, while combination with enzalutamide reversed enzalutamide-induced migration and invasion. These collective findings suggest loss of delays growth of CRPC and inhibits metastasis, and inhibition of Notch1 activation in conjunction with second-generation antiandrogen therapies could delay growth and progression of prostate cancer.
前列腺癌仍然是男性癌症相关死亡的主要原因之一。患有侵袭性疾病的患者通常接受激素剥夺治疗。尽管治疗最初非常成功，但这些男性通常在 2 到 3 年内发展为致命的去势抵抗性前列腺癌（CRPC）。CRPC 的标准治疗包括第二代抗雄激素药物，这些药物只能将患者的寿命延长几个月。深入了解导致耐药的机制对于确定侵袭性前列腺癌的新疗法至关重要。本研究确定 Notch1 是前列腺癌的治疗靶点。在侵袭性前列腺癌细胞中缺失 可降低增殖、侵袭和肿瘤球形成。用γ分泌酶抑制剂 RO4929097 或 DAPT 抑制 Notch1 活性可进一步降低前列腺癌细胞的增殖能力。在携带前列腺癌异种移植物的免疫缺陷小鼠中缺失 并联合使用 RO4929097 治疗显示出明显的肿瘤生长受损。缺失 还降低了侵袭试验和 实验中前列腺癌细胞的转移潜力。此外，用γ分泌酶抑制剂或 基因缺失与抗雄激素治疗（恩扎鲁胺或阿比特龙）协同作用，可降低前列腺癌细胞的生长。用 γ 分泌酶抑制剂联合阿比特龙可显著抑制细胞迁移和侵袭，而联合恩扎鲁胺则逆转了恩扎鲁胺诱导的迁移和侵袭。这些综合研究结果表明，缺失 可延缓 CRPC 的生长并抑制转移，抑制 Notch1 激活并与第二代抗雄激素治疗联合使用可能会延迟前列腺癌的生长和进展。
