Department of Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA.
Cell Death Dis. 2022 Aug 5;13(8):678. doi: 10.1038/s41419-022-05133-9.
Adenoid cystic carcinoma (ACC) is an aggressive salivary gland malignancy with limited treatment options for recurrent or metastatic disease. Due to chemotherapy resistance and lack of targeted therapeutic approaches, current treatment options for the localized disease are limited to surgery and radiation, which fails to prevent locoregional recurrences and distant metastases in over 50% of patients. Approximately 20% of patients with ACC carry NOTCH-activating mutations that are associated with a distinct phenotype, aggressive disease, and poor prognosis. Given the role of NOTCH signaling in regulating tumor cell behavior, NOTCH inhibitors represent an attractive potential therapeutic strategy for this subset of ACC. AL101 (osugacestat) is a potent γ-secretase inhibitor that prevents activation of all four NOTCH receptors. While this investigational new drug has demonstrated antineoplastic activity in several preclinical cancer models and in patients with advanced solid malignancies, we are the first to study the therapeutic benefit of AL101 in ACC. Here, we describe the antitumor activity of AL101 using ACC cell lines, organoids, and patient-derived xenograft models. Specifically, we find that AL101 has potent antitumor effects in in vitro and in vivo models of ACC with activating NOTCH1 mutations and constitutively upregulated NOTCH signaling pathway, providing a strong rationale for evaluation of AL101 in clinical trials for patients with NOTCH-driven relapsed/refractory ACC.
腺样囊性癌（ACC）是一种侵袭性的唾液腺癌，对于复发性或转移性疾病的治疗选择有限。由于化疗耐药和缺乏靶向治疗方法，目前对于局限性疾病的治疗选择仅限于手术和放疗，但仍无法预防超过 50%的患者发生局部复发和远处转移。大约 20%的 ACC 患者携带 NOTCH 激活突变，这些突变与独特的表型、侵袭性疾病和不良预后相关。鉴于 NOTCH 信号通路在调节肿瘤细胞行为中的作用，NOTCH 抑制剂代表了针对这部分 ACC 的一种有吸引力的潜在治疗策略。AL101（osugacestat）是一种有效的 γ-分泌酶抑制剂，可防止所有四个 NOTCH 受体的激活。虽然这种研究性新药在几种临床前癌症模型和晚期实体恶性肿瘤患者中已显示出抗肿瘤活性，但我们是第一个研究 AL101 在 ACC 中的治疗益处的。在这里，我们使用 ACC 细胞系、类器官和患者来源的异种移植模型描述了 AL101 的抗肿瘤活性。具体而言，我们发现 AL101 在具有激活的 NOTCH1 突变和持续上调的 NOTCH 信号通路的 ACC 的体外和体内模型中具有强大的抗肿瘤作用，为在临床试验中评估 AL101 治疗 NOTCH 驱动的复发性/难治性 ACC 患者提供了强有力的理由。
