Integrated Image-Guided Targeted Therapy for Refractory Ovarian Cancer

描述(申请人提供)：在治疗期间，复发癌症对传统和新型化疗药物产生多重耐药性，这是临床癌症治疗中的一个巨大挑战，特别是对妇科恶性肿瘤的有效治疗。这份R01提案描述了一种名为NMI-500的靶向、组合显像剂和治疗性纳米乳剂，旨在提供有关联合治疗在哪里积累的及时诊断信息，并为临床医生提供量化洞察，以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研究小组将合作开发这一临床可翻译的策略，最初解决复发的多药耐药表型。NMI-500使用叶酸来特异性地靶向多西紫杉醇(DTX)，并使用Gd(一种磁共振成像剂)来定位疾病以及远端转移。已知，以部分叶酸为靶点的NMI-500‘S可促进表达叶酸受体α(FR-a)的肿瘤的摄取。在正常组织中大部分缺失的FR-a已被证明在80%的复发性卵巢肿瘤中过度表达。在乳腺癌中，高FR-α的表达与不良的临床结果有关。NMI-500的成像成分将通过核磁共振造影剂Gd实现，已被证明在与纳米乳剂1结合时可以提高对比度效率。1具体目标将评估和验证组合成像/化疗产品NMI-500的成像、靶向、疗效和药代动力学。 与公共健康相关：正如PAR中所述，为一个或多个成像系统开发的纳米载体的目的包括运输治疗剂，增加了它们的设计、优化和验证的复杂性。我们的建议挑战了这样一种范式，即通过将基础科学转化为临床战略来实时检测原发和远端转移瘤的治疗积累，无法克服这种复杂性来完成创新周期。我们坚信，像NMI-500这样的复杂组合模式将成为个性化医学革命的一部分，这场革命才刚刚开始，其首要目标应该是与卵巢癌相关的令人沮丧的死亡率。在治疗过程中，复发的癌症对传统的和新型的化疗药物产生了多药耐药，这对临床癌症治疗，特别是对妇科恶性肿瘤的有效治疗是一个巨大的挑战。这份R01提案描述了一种名为NMI-500的靶向、组合显像剂和治疗性纳米乳剂，旨在提供有关联合治疗在哪里积累的及时诊断信息，并为临床医生提供量化洞察，以根据这些新信息调整治疗计划。来自两个学术组织和两个商业组织的研究小组将合作开发这一临床可翻译的策略，最初解决复发的多药耐药表型。NMI-500使用叶酸来特异性地靶向多西紫杉醇(DTX)，并使用Gd(一种磁共振成像剂)来定位疾病以及远端转移。已知，以部分叶酸为靶点的NMI-500‘S可促进表达叶酸受体α(FR-a)的肿瘤的摄取。在正常组织中大部分缺失的FR-a已被证明在80%的复发性卵巢肿瘤中过度表达。在乳腺癌中，高FR-α的表达与不良的临床结果有关。NMI-500的成像成分将通过核磁共振造影剂Gd实现，已被证明在与纳米乳剂1结合时可以提高对比度效率。1具体目标将评估和验证组合成像/化疗产品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. 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.