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.

开发用于治疗晚期头颈部鳞状细胞癌 (HNSCC) 的有效疗法仍然是一项重大挑战，并且有效的靶向疗法前景有限。NAD(P)H:醌氧化还原酶 1 (NQO1) 是一种 2 电子还原酶，在 HNSCC 中过表达，是治疗 HNSCC 的有希望的靶点。目前的 NQO1 靶向药物因其在人类患者中的氧化耐受性差而受到阻碍，强调需要更好地筛选 NQO1 生物活化小分子的氧化毒性。在此，我们描述了我们的工作，将猫科动物和猫科动物口腔鳞状细胞癌 (FOSCC) 患者纳入临床前评估过程，以便在完全人工翻译之前优先考虑具有更高耐受性和有效性的先导化合物。具体来说，我们的数据表明，IB-DNQ 是一种 NQO1 靶向小分子，在 FOSCC 患者中具有良好的耐受性，并且在概念验证单药和放射治疗组合队列中显示出对 FOSCC 肿瘤的有希望的初步疗效。此外，FOSCC 肿瘤适合评估各种靶诱导偶联假说，本文通过姑息性放疗调节 NQO1 水平证明了这一点。猫科动物及其自然发生的肿瘤的使用为 NQO1 靶向方法的临床前药物开发提供了一种有趣但经常未被充分利用的工具，并且在评估其他抗癌策略方面具有更广泛的应用。在 FOSCC 患者中具有良好的耐受性，并且在概念验证单药和放射治疗组合队列中显示出对 FOSCC 肿瘤的有希望的初步疗效。此外，FOSCC 肿瘤适合评估各种靶诱导偶联假说，本文通过姑息性放疗调节 NQO1 水平证明了这一点。猫科动物及其自然发生的肿瘤的使用为 NQO1 靶向方法的临床前药物开发提供了一种有趣但经常未被充分利用的工具，并且在评估其他抗癌策略方面具有更广泛的应用。在 FOSCC 患者中具有良好的耐受性，并且在概念验证单药和放射治疗组合队列中显示出对 FOSCC 肿瘤的有希望的初步疗效。此外，FOSCC 肿瘤适合评估各种靶诱导偶联假说，本文通过姑息性放疗调节 NQO1 水平证明了这一点。猫科动物及其自然发生的肿瘤的使用为 NQO1 靶向方法的临床前药物开发提供了一种有趣但经常未被充分利用的工具，并且在评估其他抗癌策略方面具有更广泛的应用。