Targeted Therapy for Head and Neck Cancer

头颈癌的靶向治疗

• 批准号: 10213008
• 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/10213008
• 关键词: Affinity; Automobile Driving; Cancer Model; Cancer Patient; Cell Culture Techniques; Cell Death; Cells; Cessation of life; Clinical Trials; 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; Prognosis; Proteins; Quinones; Radiation; Reactive Oxygen Species; Recurrence; Series; Structure-Activity Relationship; Therapeutic; Therapeutic Index; Toxic effect; Translating; Trastuzumab; Variant; Work; base; bone; bone invasion; cancer cell; cytotoxic; data reduction; design; efficacy evaluation; experimental study; human disease; in silico; in vivo; innovation; malignant breast neoplasm; melanoma; mouse model; novel; overexpression; patient derived xenograft model; 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.

头颈鳞状细胞癌的治疗进展甚微 几十年来（HNSCC），对于这种致命的癌症还没有有效的靶向疗法。这 在高比例的原发性 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，以及被 NQO1 毒性的化合物 有可能为绝望的患者群体诱导显着的肿瘤消退。我们已经获得了 大量数据显示天然产物脱氧苯醌（DNQ）及其衍生物 对表达 NQO1 的细胞具有强效细胞毒性。由于 NQO1 在 HNSCC 中表达升高，但在 HNSCC 中表达较低 DNQ及其衍生物具有作为HNSCC靶向药物的潜力。此外 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， 在小鼠癌症模型以及令人兴奋的自发性癌症宠物猫中进行毒性和功效评估 HNSCC。猫科动物 HNSCC 与人类疾病非常相似，被认为是一种明显更常见的疾病。 具有代表性和挑战性的临床前模型，因此我们的数据显示 DNQ 衍生物的活性 这些以 NQO1 依赖性方式患有自发性 HNSCC 的宠物猫非常有希望。 DNQ 及其 迄今为止我们发现的衍生物不具备成为药物的适当治疗指数，即 它们的 NQO1 独立毒性限制了小鼠和猫体内的剂量。我们有 实验排除了不依赖于 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 还原 DNQ 介导的。在此处 我们提出了一项全面的计划来扩大 DNQ 的治疗指数并转化该药物类别 走向人体临床试验。在具体目标 1 中，我们结合使用结构-活性关系和 通过计算机建模设计 80 种新颖的 DNQ 衍生物，预计这些衍生物对于 P450R 来说是较差的底物 不影响其 NQO1 活性。这些化合物将通过一系列分层的单元移动 培养和患者来源的异种移植（具体目标 2）实验，其中最重要的化合物是 在特定目标 3 中对患有 HNSCC 的宠物猫进行了评估。我们的目标是确定一种适合的衍生物 在资助期结束前转化为人体临床试验。这种高度集中、假设驱动的 该提案可以为 HNSCC 提供第一个有效的靶向治疗；这将是一个重大突破 对于这个服务严重不足的患者群体。