Integrated Image-Guided Targeted Therapy for Refractory Ovarian Cancer

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了多药耐药，这是临床癌症治疗的一个巨大挑战，特别是对妇科恶性肿瘤的有效治疗。该R01提案描述了一种靶向、联合显像剂和治疗性纳米乳，命名为NMI-500，旨在提供及时的诊断信息，了解联合递送治疗的积累情况，并为临床医生提供定量的见解，根据这些新信息调整治疗计划。来自两个商业组织和两个学术组织的一组研究人员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），而钆（Gd）是一种MR显像剂，用于局部疾病和远端转移。已知NMI-500靶向叶酸片段可改善表达叶酸受体α (FR-a)的肿瘤对叶酸的摄取。FR- a在正常组织中基本不存在，但在80%的复发性卵巢肿瘤中呈过表达。在乳腺癌中，高fr -a表达与较差的临床结果有关。NMI-500的成像成分将与MRI造影剂Gd一起实现，该造影剂已被证明与纳米乳液结合可以提高造影剂的对比度具体目标将评估和验证成像/化疗联合产品NMI-500的成像、靶向、疗效和药代动力学。

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.