Integrated Image-Guided Targeted Therapy for Refractory Ovarian Cancer

难治性卵巢癌的综合影像引导靶向治疗

• 批准号: 8248798
• 负责人: Mansoor M Amiji
• 金额: $ 54.02万
• 依托单位: NEMUCORE MEDICAL INNOVATIONS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8248798
• 关键词: Address; Adverse effects; Basic Science; Cancer Model; Cancer Patient; Clinic; Clinical; Clinical Trials; Complex; Contrast Media; Data; Diagnostic; Disease Progression; Distal; Dosage Forms; Dose; Drug Kinetics; Epithelial ovarian cancer; Folate; Gadolinium; Goals; Human; Image; In Vitro; Investigation; Knowledge; Laboratories; Light; Link; Localized Disease; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of ovary; Medicine; Modality; Modeling; Morphology; Multi-Drug Resistance; Mus; Nanotechnology; Neoplasm Metastasis; Newly Diagnosed; Normal tissue morphology; Outcome; Paclitaxel; Pharmaceutical Preparations; Phenotype; Plasma; Polysorbate 80; Rattus; Recurrence; Recurrent Malignant Neoplasm; Recurrent disease; Recurrent tumor; Refractory; Regimen; Research Personnel; Safety; Solutions; System; Technology; Therapeutic Agents; Time; Tissues; Toxic effect; Transgenic Mice; Translating; Treatment Efficacy; Treatment Protocols; Validation; Xenograft procedure; base; cancer therapy; chemotherapeutic agent; combat; cytotoxicity; design; docetaxel; effective therapy; exhaust; experience; gadolinium oxide; human FOLR1 protein; improved; in vivo; innovation; insight; intraperitoneal; malignant breast neoplasm; man; mortality; mouse model; nanocarrier; nanoemulsion; nanomedicine; novel; ovarian neoplasm; preclinical study; public health relevance; residence; tumor; uptake

DESCRIPTION (provided by applicant): During treatment recurrent cancers build up multidrug resistance to conventional and novel chemotherapeutic agents representing a formidable challenge in clinical cancer therapy, especially for the effective treatment of gynecological malignancies. This R01 proposal describes a targeted-, combination imaging agent and therapeutic nanoemulsion, designated NMI-500, designed to provide timely diagnostic information on where the co-deliver treatment is accumulating and provide clinicians the quantitative insight to adjust treatment schedules in light of this new information. A team of investigators from two commercial and two academic organizations will collaborate to develop this clinically translatable strategy, initially addressing recurrent multidrug resistant phenotype. NMI-500 uses folate to specifically target docetaxel (DTX), and gadolinium (Gd) an MR imaging agent to localized disease as well as distal metastases. NMI-500's targeting moiety folate is known to improve uptake by tumors expressing folate receptor alpha (FR-a). FR- a, largely absent from normal tissue, has been shown to be over expressed on >80% of recurring ovarian tumors. In breast cancer high FR-an expression has been linked to poor clinical outcomes. The imaging component of NMI-500 will be achieved with the MRI contrast agent Gd, which has been shown to enhance contrast efficiency when conjugated to a nanoemulsion.1 Specific aims will assess and validate the imaging, targeting, efficacy and pharmacokinetics of the combination imaging/chemotherapeutic product, NMI-500. PUBLIC HEALTH RELEVANCE: As stated in the PAR ".nano-carriers developed for one or more imaging systems for the purposes that include transport of therapeutic agents, adds complexity to their design, optimization and validation". Our proposal challenges the paradigm that such complexity cannot be overcome to complete the cycle of innovation by translating basic science into clinical strategies to detect in real-time the accumulation of therapy at the primary and distal metastasises. We strongly believe complex combination modalities like NMI-500 will be part of the personalized medicine revolution that is only now beginning and its first target should be the dismal mortality rates associated with ovarian cancer. During treatment recurrent cancers build up multidrug resistance to conventional and novel chemotherapeutic agents representing a formidable challenge in clinical cancer therapy, especially for the effective treatment of gynecological malignancies. This R01 proposal describes a targeted-, combination imaging agent and therapeutic nanoemulsion, designated NMI-500, designed to provide timely diagnostic information on where the co-deliver treatment is accumulating and provide clinicians the quantitative insight to adjust treatment schedules in light of this new information. A team of investigators from two academic and two commercial organizations will collaborate to develop this clinically translatable strategy, initially addressing recurrent multidrug resistant phenotype. NMI-500 uses folate to specifically target docetaxel (DTX), and gadolinium (Gd) an MR imaging agent to localized disease as well as distal metastases. NMI-500's targeting moiety folate is known to improve uptake by tumors expressing folate receptor alpha (FR-a). FR- a, largely absent from normal tissue, has been shown to be over expressed on >80% of recurring ovarian tumors. In breast cancer high FR-an expression has been linked to poor clinical outcomes. The imaging component of NMI-500 will be achieved with the MRI contrast agent Gd, which has been shown to enhance contrast efficiency when conjugated to a nanoemulsion.1 Specific aims will assess and validate the imaging, targeting, efficacy and pharmacokinetics of the combination imaging/chemotherapeutic product, NMI-500.

描述（由申请人提供）：在治疗过程中，复发性癌症对传统和新型化疗药物产生多药耐药性，这是临床癌症治疗中的一个巨大挑战，特别是对于妇科恶性肿瘤的有效治疗。该R 01提案描述了一种靶向、联合成像剂和治疗性纳米乳剂，命名为NMI-500，旨在提供关于联合递送治疗在何处累积的及时诊断信息，并为临床医生提供定量见解，以根据该新信息调整治疗方案。来自两个商业组织和两个学术组织的研究人员团队将合作开发这种临床可翻译的策略，最初解决复发性多药耐药表型。 NMI-500使用叶酸特异性靶向多西他赛（DTX），使用钆（Gd）作为MR成像剂靶向局部疾病和远端转移。已知NMI-500的靶向部分叶酸盐可改善表达叶酸盐受体α（FR-α）的肿瘤的摄取。FR-α在正常组织中基本上不存在，已显示在>80%的复发性卵巢肿瘤上过表达。在乳腺癌中，高FR-α表达与不良的临床结果有关。NMI-500的成像成分将通过MRI造影剂Gd实现，该造影剂已被证明与纳米乳剂结合时可增强造影效率。1具体目标将评估和验证成像/化疗组合产品NMI-500的成像、靶向、疗效和药代动力学。 公共卫生相关性：正如PAR中所述，“为一个或多个成像系统开发的纳米载体，其目的包括输送治疗剂，增加了其设计、优化和验证的复杂性”。我们的提案挑战了这样一种范式，即通过将基础科学转化为临床策略来实时检测原发和远端转移的治疗积累，无法克服这种复杂性来完成创新周期。我们坚信，像NMI-500这样的复杂组合方式将成为个性化医疗革命的一部分，这场革命现在才刚刚开始，其第一个目标应该是卵巢癌相关的低死亡率。 在治疗过程中，复发性癌症对传统和新型化疗药物产生多药耐药性，这对临床癌症治疗，特别是有效治疗妇科恶性肿瘤来说是一个巨大的挑战。该R 01提案描述了一种靶向、联合成像剂和治疗性纳米乳剂，命名为NMI-500，旨在提供关于联合递送治疗在何处累积的及时诊断信息，并为临床医生提供定量见解，以根据该新信息调整治疗方案。来自两个学术机构和两个商业机构的研究人员团队将合作开发这种临床可翻译的策略，最初解决复发性多药耐药表型。 NMI-500使用叶酸特异性靶向多西他赛（DTX），使用钆（Gd）作为MR成像剂靶向局部疾病和远端转移。已知NMI-500的靶向部分叶酸盐可改善表达叶酸盐受体α（FR-α）的肿瘤的摄取。FR-α在正常组织中基本上不存在，已显示在>80%的复发性卵巢肿瘤上过表达。在乳腺癌中，高FR-α表达与不良的临床结果有关。NMI-500的成像成分将通过MRI造影剂Gd实现，该造影剂已被证明与纳米乳剂结合时可增强造影效率。1具体目标将评估和验证成像/化疗组合产品NMI-500的成像、靶向、疗效和药代动力学。