Utilizing feline oral squamous cell carcinoma patients to develop NQO1-targeted therapy.
Utilizing feline oral squamous cell carcinoma patients to develop NQO1-targeted therapy.
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DOI：
10.1016/j.neo.2021.06.008
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Fan TM
中科院分区：
文献类型：
--
作者：
Lundberg AP;Boudreau MW;Selting KA;Chatkewitz LE;Samuelson J;Francis JM;Parkinson EI;Barger AM;Hergenrother PJ;Fan TM
开发治疗晚期头颈部鳞状细胞癌（HNSCC）的有效疗法仍然是一个重大挑战，并且有效靶向疗法的前景有限。NAD（P）H：醌氧化还原酶1（NQO 1）是一种2-电子还原酶，在HNSCC中过表达，并作为治疗HNSCC的有希望的靶点。目前NQO 1靶向药物在人类患者中的氧化耐受性较差，这表明需要更好地对NQO 1生物活化小分子的氧化毒性进行临床前筛选。在本文中，我们描述了我们的工作，包括猫和猫口腔鳞状细胞癌（FOSCC）患者在临床前评估过程中，优先考虑先导化合物的耐受性和有效性增加之前，完全人类翻译。具体而言，我们的数据表明，IB-DNQ，一种NQO 1靶向小分子，在FOSCC患者中耐受良好，并在概念验证单药和放疗联合队列中显示出对FOSCC肿瘤有希望的初始疗效。此外，FOSCC肿瘤适合于评估各种靶诱导偶联体假说，本文通过姑息性放疗调节NQO 1水平来证明。使用猫科动物及其自然发生的肿瘤为NQO 1靶向方法的临床前药物开发提供了一种有趣的，通常未被充分利用的工具，并在评估其他抗癌策略方面具有更广泛的应用。
Developing effective therapies for the treatment of advanced head-and-neck squamous cell carcinoma (HNSCC) remains a major challenge, and there is a limited landscape of effective targeted therapies on the horizon. NAD(P)H:quinone oxidoreductase 1 (NQO1) is a 2-electron reductase that is overexpressed in HNSCC and presents as a promising target for the treatment of HNSCC. Current NQO1-targeted drugs are hindered by their poor oxidative tolerability in human patients, underscoring a need for better preclinical screening for oxidative toxicities for NQO1-bioactivated small molecules. Herein, we describe our work to include felines and feline oral squamous cell carcinoma (FOSCC) patients in the preclinical assessment process to prioritize lead compounds with increased tolerability and efficacy prior to full human translation. Specifically, our data demonstrate that IB-DNQ, an NQO1-targeted small molecule, is well-tolerated in FOSCC patients and shows promising initial efficacy against FOSCC tumors in proof-of-concept single agent and radiotherapy combination cohorts. Furthermore, FOSCC tumors are amenable to evaluating a variety of target-inducible couplet hypotheses, evidenced herein with modulation of NQO1 levels with palliative radiotherapy. The use of felines and their naturally-occurring tumors provide an intriguing, often underutilized tool for preclinical drug development for NQO1-targeted approaches and has broader applications for the evaluation of other anticancer strategies.
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DOI：
10.1093/icb/20.1.199
发表时间：
1980-01-01
期刊：
AMERICAN ZOOLOGIST
影响因子：
--
作者：
BUNN, HF
通讯作者：
BUNN, HF
DOI：
10.1073/pnas.90.15.7200
发表时间：
1993-08-01
影响因子：
11.1
作者：
BOOTHMAN, DA;MEYERS, M;LEE, SW
通讯作者：
LEE, SW
影响因子：
158.5
作者：
Bernier, J;Domenge, C;van Glabbeke, M
通讯作者：
van Glabbeke, M
影响因子：
4.8
作者：
Choi, Eun K.;Terai, Kaoru;Park, Heon Joo
通讯作者：
Park, Heon Joo
影响因子：
158.5
作者：
Bonner, JA;Harari, PM;Ang, KK
通讯作者：
Ang, KK