Targeted Therapy for Head and Neck Cancer

头颈癌的靶向治疗

基本信息

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
项目类别：
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

项目摘要

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。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 毒性的化合物我们已经获得了对绝望的患者群体诱导肿瘤显着消退的潜力。大量数据显示天然产物脱氧苯醌（DNQ）及其衍生物在表达 NQO1 的细胞中具有强效细胞毒性，因为 NQO1 在 HNSCC 中表达升高，但在 HNSCC 中表达较低。除了正常组织外，DNQ 及其衍生物还具有作为 HNSCC 靶向药物的潜力。 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 衍生物在这些以 NQO1 依赖性方式患有自发性 HNSCC 的宠物猫非常有希望。迄今为止，我们已经鉴定出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。实验排除了不依赖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。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在具体目标 1 中，我们结合了结构-活性关系和通过计算机建模设计 80 种新型 DNQ 衍生物，预计这些衍生物对于 P450R 来说是较差的底物这些化合物将在不影响其 NQO1 活性的情况下通过一系列分层的细胞。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时转化为人体临床试验。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。