Developing alternative approaches to reduce retinal toxicity and prevent vision loss in the treatment of intraocular retinoblastoma

开发替代方法来减少眼内视网膜母细胞瘤治疗中的视网膜毒性并预防视力丧失

• 批准号: 9440442
• 负责人: Anthony Brent Daniels
• 金额: $ 19.19万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9440442
• 关键词: Address; Adverse effects; Affect; Animal Cancer Model; Animal Model; Animals; Antineoplastic Agents; Award; Biology; Biometry; Blindness; Blood Vessels; Cell Line; Cells; Child; Clinical; Clinical Research; Country; Diffuse; Dose; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Drug toxicity; Drug usage; Effectiveness; Electrophysiology (science); Electroretinography; Ensure; Evaluation; Experimental Models; Eye; Eye Neoplasms; Fertility; Fluorescein Angiography; Fundus photography; Future; Genetic; Goals; Histopathology; Human; In Vitro; Income; Injections; Intraocular retinoblastoma; Intravenous; Lead; Life; Long-Term Effects; Malignant Childhood Neoplasm; Malignant Neoplasms; Mass Spectrum Analysis; Maximum Tolerated Dose; Measures; Melphalan; Mentors; Methods; Modality; Modeling; Monitor; Morbidity - disease rate; Neutropenia; New Agents; Optical Coherence Tomography; Oryctolagus cuniculus; Outcome; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Quality of life; Regimen; Reproducibility; Research; Research Design; Research Personnel; Retina; Retinal; Retinal Neoplasms; Retinoblastoma; Route; Safety; Savings; Scientist; Seeds; Structure; Survival Rate; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Toxic effect; Training; Translating; Translations; Tumor Biology; Tumor Burden; United States Food and Drug Administration; Vision; Visual; alpha-Thalassemia; base; burden of illness; cancer therapy; career development; chemotherapeutic agent; chemotherapy; clinical practice; cytotoxicity; drug candidate; drug discovery; drug efficacy; drug testing; efficacy study; experience; fighting; improved; in situ imaging; in vivo; intravitreal injection; malignant neoplasm of eye; novel; novel therapeutics; outcome forecast; pre-clinical; preclinical study; prevent; safety testing; skills; systemic toxicity; targeted agent; tumor

Retinoblastoma (RB) is the most common intraocular malignancy in children. The recent introduction of intra- arterial chemotherapy (IAC) and intravitreal injections, both using melphalan-based regimens, has improved globe survival for eyes with advanced RB, while avoiding the systemic toxicities of intravenous chemotherapy. However, melphalan is toxic to the retina and retinal vasculature, and both treatments are associated with many ocular side effects, potentially resulting in life-long loss of vision. The goal of this research is to identify alternative drugs that are less toxic to the ocular structures but remain effective against intraocular RB, for use via IAC and intravitreal injection. In rabbits, we have developed the only small animal model of IAC, and have demonstrated excellent ocular penetration and reproducible pharmacokinetics (PK) for melphalan. We have also developed a rabbit model of RB that develops both retinal tumors and vitreous seeds grown from human RB cell lines, recapitulating features found in patients with advanced RB. Using these novel models, we plan to determine the PK, retinal/retinal vascular toxicity profiles, and efficacy of a selected group of chemotherapeutic agents that already have FDA-approval. Focusing on FDA-approved drugs will allow rapid translation of our findings into clinical practice. Both vitreous and intra-retinal drug concentrations and PK curves will be calculated for each drug following both IAC or intravitreal injection, using traditional mass spectrometry and a novel in situ imaging mass spectrometry technique that was developed at Vanderbilt. Once the PK curves have been calculated, the maximum tolerable dose (MTD) for each drug will be calculated for both IAC and for repeated intravitreal injections. Functional and structural ocular toxicity will be measured using a comprehensive panel of techniques. A robust Bayesian Continual Reassessment Method clinical study design will be employed. The MTD will then be used in studies of the efficacy of each drug, given by either IAC or intravitreal injection, for the treatment of RB in the above rabbit models. Following identification of safe and effective target doses in vivo in our rabbit model, we will confirm the absence of retinal toxicity using a cutting edge technology that allows drug toxicity to be monitored over time in ex vivo human retinal tissues that can be kept alive in a supportive perfusate for functional evaluation. This ensures that these drugs are safe for human eyes (not just rabbits). Dr. Daniels brings experience with ocular tumor biology and genetics, as well as clinical expertise with IAC for RB. The long-term goal of his research is to develop safer, pathway-targeted agents for the treatment of RB. This Mentored Clinical Scientist Research Career Development (K08) Award will allow Dr. Daniels to be mentored by a world-class team of mentors, who have extensive expertise in retinal biology, tumor biology and therapeutics, and in the preclinical assessment of antineoplastic agents and intraocular drugs. Through a combination of hands-on experimentation and didactics, Dr. Daniels will develop necessary skills in the use of animal models for preclinical studies, in vivo assessment of retinal toxicity and efficacy, and biostatistics, while developing a comprehensive drug-testing platform that can be used to assess novel compounds in the future.

视网膜母细胞瘤（RB）是儿童最常见的眼内恶性肿瘤。最近引入了内部 使用基于Melphalan的方案的动脉化疗（IAC）和玻璃体内注射均已改善球球 晚期RB眼睛的生存，同时避免了静脉化疗的全身毒性。然而， Melphalan对视网膜和视网膜脉管系统有毒，这两种处理都与许多眼侧有关 影响，可能导致终身视力丧失。这项研究的目的是确定替代药物 对眼睛结构的毒性较小，但对眼内RB保持有效，用于通过IAC和玻璃体内使用 注射。在兔子中，我们开发了唯一的IAC动物模型，并且表现出了极好的表现 梅尔法兰（Melphalan）的眼部渗透和可再现药代动力学（PK）。我们还开发了兔子模型 RB的RB形成了视网膜肿瘤和从人RB细胞系生长的玻璃体种子，概括特征 在患有晚期RB的患者中发现。使用这些新型模型，我们计划确定PK，视网膜/视网膜血管 已经具有FDA批准的一组化学治疗剂的毒性谱和功效。 专注于FDA批准的药物将使我们的发现快速转化为临床实践。均玻璃和 在IAC或玻璃体内，将计算每种药物的视网膜内药物浓度和PK曲线 注射，使用传统的质谱和一种新颖的原位成像质谱技术 在范德比尔特开发。一旦计算了PK曲线，每个 将针对IAC和重复的玻璃体内注射计算药物。功能性和结构性眼毒性 将使用全面的技术面板来测量。强大的贝叶斯持续重新评估方法 将采用临床研究设计。然后，MTD将用于研究每种药物疗效的研究，由 IAC或玻璃体内注射，用于在上述兔模型中治疗RB。确定安全 在我们的兔模型中，体内有效靶剂量，我们将使用切割确认缺乏视网膜毒性 边缘技术，该技术允许药物毒性随着时间的流逝而在体内人类视网膜组织中受到监测 活在支持性灌注液中进行功能评估。这样可以确保这些药物对人眼睛安全（不是 只是兔子）。丹尼尔斯博士带来了眼部肿瘤生物学和遗传学的经验，以及临床专业知识 IAC用于RB。他的研究的长期目标是为RB的治疗开发更安全的，符合途径的药物。 这项指导的临床科学家研究职业发展（K08）奖将使Daniels博士成为 由世界一流的导师团队指导，他们在视网膜生物学，肿瘤生物学和 在抗肿瘤药和眼内药物的临床前评估中。通过一个 动手实验和教学法的结合，丹尼尔斯博士将发展使用必要的技能 临床前研究的动物模型，视网膜毒性和功效的体内评估以及生物统计学 开发一个可用于评估新化合物的综合药物测试平台。