Targeted Therapy for Head and Neck Cancer

头颈癌的靶向治疗

• 批准号: 9764348
• 负责人: Paul Hergenrother
• 金额: $ 36.74万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9764348
• 关键词: Affinity; Automobile Driving; Cancer Model; Cancer Patient; Cell Culture Techniques; Cell Death; Cells; Cessation of life; Clinical Trials; Computer Simulation; Data; Development; Disease; Disease Progression; Dose; Drug Kinetics; Drug Metabolic Detoxication; Drug Targeting; Electrons; Enzymes; Evaluation; Family Felidae; Felis catus; Funding; Generations; Gleevec; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; Human Pathology; Hydroquinones; In Vitro; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Modeling; Modernization; Mus; Mutation; NQO1 gene; Natural Products; Normal tissue morphology; Outcome; Oxidoreductase; Parents; Patients; Pharmaceutical Preparations; Population; Pre-Clinical Model; Process; Proteins; Quinones; Radiation; Reactive Oxygen Species; Recurrence; Series; Structure-Activity Relationship; Therapeutic; Therapeutic Index; Toxic effect; Translating; Trastuzumab; Variant; Work; Xenograft Model; Xenograft procedure; base; bone; bone invasion; cancer cell; cytotoxic; data reduction; design; experimental study; human disease; in vivo; innovation; malignant breast neoplasm; melanoma; mouse model; novel; outcome forecast; overexpression; patient population; patient response; response; small molecule; targeted agent; targeted treatment; translation to humans; translational model; tumor; two-arm study

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.

治疗头颈鳞状细胞癌几乎没有取得进展 （HNSCC）几十年来，这种致命的癌症没有有影响力的靶向疗法。 在高比例的原发性HNSCC肿瘤中，已经观察到酶NQO1的过表达， 包括在那些预后最差的HNSCC患者中，因此由NQO1毒 有可能诱导绝望的患者人群引起明显的肿瘤回归。我们已经获得了 大量数据显示了天然产物脱氧尼博酮（DNQ）及其衍生物是 在表达NQO1的细胞中潜在的细胞毒性。由于HNSCC中的NQO1升高，但在 正常组织，DNQ及其衍生物具有HNSCC的靶向药物的潜力。此外 关于DNQ和衍生物的显着体外和细胞培养数据，我们还制作了药代动力学， 癌症小鼠模型的毒性和效率评估，令人兴奋地在具有赞助的宠物猫中 HNSCC。猫HNSCC与人类疾病非常相似，被认为是明显的 代表性和挑战前临床模型，因此我们的数据显示了DNQ衍生物的活性 这些以NQO1依赖性方式具有赞助HNSCC的宠物猫非常承诺。 DNQ及其 到目前为止，我们已经确定的衍生物还没有成为药物的适当治疗指数，也就是说 他们的NQO1无关毒性限制了可以在体内给小鼠和猫服用的剂量。我们有 实验性地排除了独立于NQO1的细胞死亡的各种可能性，我们的实验 表明这种毒性是由单电子还原酶P450R降低DNQ介导的。在此处 我们提出了一个全面的计划，以扩大DNQ的治疗指数并翻译此药物类别 进行人类临床试验。在特定目的1中，我们使用结构活性关系和 在设计80种新型DNQ衍生物的硅建模中，预计P450R的底物更糟 没有损害其NQO1活性。这些化合物将通过一系列分层移动 培养和患者衍生的源（特定目标2）实验，最高化合物为 在特定目标3中用HNSCC评估的宠物猫。我们的目标是确定适合的衍生物 在资金期结束之前转化为人类临床试验。这种紧密关注的假设驱动 提案可以为HNSCC提供首次有影响力的目标疗法；这将是一个重大突破 对于这个服务不足的患者人群。