Targeted Therapy for Head and Neck Cancer

头颈部鳞状细胞癌的治疗进展甚微 (HNSCC)已经几十年了，而且还没有对这种致命癌症进行有效的靶向治疗。这个 在高比例的原发HNSCC肿瘤中观察到NQO1酶的过度表达， 包括那些预后最差的HNSCC患者，因此被NQO1毒化的化合物 有可能在绝望的患者群体中诱导显著的肿瘤消退。我们已经获得了 大量数据表明，天然产物脱氧苯二酚(DNQ)及其衍生物是 在表达NQO1的细胞中具有潜在的细胞毒性。当NQO1在HNSCC中高表达，但在HNSCC中低表达 正常组织、DNQ及其衍生物具有作为HNSCC靶向药物的潜力。除了……之外 关于DNQ及其衍生物的重要体外和细胞培养数据，我们还进行了药代动力学研究， 对小鼠癌症模型的毒性和疗效评估，以及令人兴奋的是，在宠物猫的自发性 HNSCC。猫的HNSCC与人类的疾病非常相似，被认为是明显更多的 具有代表性和挑战性的临床前模型，因此我们的数据显示了DNQ衍生物在 这些患有NQO1依赖的自发性HNSCC的宠物猫非常有前途。DNQ及其ITS 到目前为止，我们鉴定的衍生物没有合适的治疗指数成为药物，也就是说， 它们的NQO1非依赖性毒性限制了在体内给小鼠和猫的剂量。我们有 实验排除了NQO1非依赖性细胞死亡的各种可能性，我们的实验 提示这种毒性是通过单电子还原酶P450R还原DNQ来实现的。在此 我们提出了一个全面的计划，以扩大DNQ的治疗指数，并翻译这一药物类别 进行人体临床试验。在具体目标1中，我们使用结构-活性关系和 在计算机模拟中设计80种新的DNQ衍生物，这些衍生物被预测为P450R的更差底物 而不会影响他们的NQO1活动。这些化合物将通过一系列层叠的细胞 培养和患者来源的异种移植(特定目标2)实验，顶级化合物为 在患有HNSCC的宠物猫身上进行特定目标的评估3。我们的目标是识别出一种适合于 在资助期结束前转化为人体临床试验。这是一种高度集中的、假设驱动的 该提案可能为HNSCC提供第一个有效的靶向治疗；这将是一个重大突破 为这群严重缺乏医疗服务的病人服务。

Little progress has been made in the treatment of head-and-neck squamous cell carcinoma (HNSCC) in decades, and there are no impactful targeted therapies for this deadly cancer. The overexpression of the enzyme NQO1 has been observed in a high percentage of primary HNSCC tumors, including in those HNSCC patients with the worst prognoses, and thus compounds that are toxified by NQO1 have the potential to induce marked tumor regression for a desperate patient population. We have obtained a substantial amount of data showing the natural product deoxynyboquinone (DNQ) and its derivatives are potently cytotoxic in cells that express NQO1. As NQO1 is elevated in HNSCC but has low expression in normal tissue, DNQ and its derivatives have the potential as targeted drugs for HNSCC. In addition to significant in vitro and cell culture data on DNQ and derivatives, we have also made pharmacokinetic, toxicity, and efficacy assessments in mouse models of cancer and – excitingly – in pet cats with spontaneous HNSCC. Feline HNSCC is very similar to the human disease and is regarded as a significantly more representative and challenging pre-clinical model, thus our data showing activity of a DNQ derivative in these pet cats with spontaneous HNSCC in a NQO1-dependent fashion is very promising. DNQ and its derivatives we have identified thus far do not have the proper therapeutic index to become drugs, that is, their NQO1-independent toxicity limits the dose that can be given to mice and cats in vivo. We have experimentally ruled out various possibilities for the NQO1-independent cell death, and our experiments suggest that this toxicity is mediated by the reduction of DNQ by the one-electron reductase P450R. Herein we propose a comprehensive plan to widen the therapeutic index for DNQ and translate this drug class toward human clinical trials. In Specific Aim 1 we use a combination of structure-activity relationships and in silico modeling to design 80 novel DNQ derivatives that are predicted to be worse substrates for P450R without compromising their NQO1 activity. These compounds will be moved through a tiered series of cell culture, and patient-derived xenograft (Specific Aim 2) experiments, with the top compounds being evaluated in pet cats with HNSCC in Specific Aim 3. Our goal is to have identified a derivative suitable for translation to human clinical trials by the end of the funding period. This tightly-focused, hypothesis-driven proposal could provide the first impactful targeted therapy for HNSCC; this would be a major breakthrough for this vastly underserved patient population.