AL101, a gamma-secretase inhibitor, has potent antitumor activity against adenoid cystic carcinoma with activated NOTCH signaling.
AL101, a gamma-secretase inhibitor, has potent antitumor activity against adenoid cystic carcinoma with activated NOTCH signaling.
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DOI：
10.1038/s41419-022-05133-9
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发表时间：
2022-08-05
影响因子：
9
通讯作者：
Izumchenko, Evgeny
中科院分区：
文献类型：
--
作者：
Ferrarotto, Renata;Mishra, Vasudha;Herz, Elad;Yaacov, Adar;Solomon, Oz;Rauch, Rami;Mondshine, Adi;Motin, Maria;Leibovich-Rivkin, Tal;Davis, Matti;Kaye, Joel;Weber, Christopher R.;Shen, Le;Pearson, Alexander T.;Rosenberg, Ari J.;Chen, Xiangying;Singh, Alka;Aster, Jon C.;Agrawal, Nishant;Izumchenko, Evgeny
腺样囊性癌（ACC）是一种侵袭性涎腺恶性肿瘤，复发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，目前对局限性疾病的治疗选择仅限于手术和放疗，超过50%的患者无法预防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信号在调节肿瘤细胞行为中的作用，NOTCH抑制剂代表了一种有吸引力的潜在治疗策略。AL101是一种有效的γ-分泌酶抑制剂，可阻止所有四种NOTCH受体的激活。虽然这种正在研究的新药已经在几种临床前癌症模型和晚期实体恶性肿瘤患者中显示出抗肿瘤活性，但我们是第一个研究AL101在ACC中的治疗益处的人。在这里，我们用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。具体来说，我们发现AL101在体外和体内激活NOTCH1突变和组成性上调NOTCH信号通路的ACC模型中具有强大的抗肿瘤作用，为在NOTCH1驱动的复发/难治性ACC患者的临床试验中评估AL101提供了强有力的理论依据。
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.
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影响因子：
4.3
作者：
Eden E;Lipson D;Yogev S;Yakhini Z
通讯作者：
Yakhini Z
DOI：
10.1200/jco.2016.67.5264
发表时间：
2017-01-20
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
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通讯作者：
Heymach JV
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
DOI：
10.1158/1078-0432.ccr-20-1192
发表时间：
2021-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Ferrarotto R;Mitani Y;McGrail DJ;Li K;Karpinets TV;Bell D;Frank SJ;Song X;Kupferman ME;Liu B;Lee JJ;Glisson BS;Zhang J;Aster JC;Lin SY;Futreal PA;Heymach JV;El-Naggar AK
通讯作者：
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影响因子：
4.4
作者：
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通讯作者：
Caldas C