Targeted Combination Therapy for Breast Cancer

乳腺癌靶向联合治疗

• 批准号: 9186502
• 负责人: Song Li
• 金额: $ 31.33万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-02 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9186502
• 关键词: 2-tyrosine; Abraxane; Address; Albumins; Alcohols; Anti-Inflammatory Agents; Antidiabetic Drugs; Apoptosis; Benzoquinones; Biological Models; Breast Cancer therapy; CASP3 gene; CASP9 gene; Camptothecin; Caspase; Clinical; Combined Modality Therapy; Cremophor; Development; Doxorubicin; Drug Kinetics; ERBB2 gene; Effectiveness; Embelia; Excipients; Formulation; Goals; Histamine; Human; Hydroxyl Radical; Hypersensitivity; In Vitro; Lead; Malignant neoplasm of lung; Malignant neoplasm of prostate; Maximum Tolerated Dose; Mediating; Micelles; Monoclonal Antibodies; Neoplasms in Vascular Tissue; Paclitaxel; Particle Size; Penetration; Pharmaceutical Preparations; Phase; Phenotype; Polymers; Proteins; RNA Interference; Radiation; Reaction; Ribes; Safety; Solubility; Structure; Structure-Activity Relationship; System; TNFSF10 gene; Therapeutic; Therapeutic Index; Toxic effect; Trastuzumab; Treatment Efficacy; Tyrosine Kinase Inhibitor; Water; Xenograft procedure; acquired drug resistance; antitumor effect; base; cancer cell; cancer type; cell type; chemotherapeutic agent; cost; embelin; improved; in vivo; inflammatory breast cancer; interfacial; killings; knock-down; lapatinib; malignant breast neoplasm; mouse model; nanoformulation; novel; overexpression; protein expression; public health relevance; systemic toxicity; targeted delivery; tumor; x-linked inhibitor of apoptosis protein

DESCRIPTION (provided by applicant): Paclitaxel (PTX) is the first-line chemotherapeutic agent for various types of cancers including breast cancer (BCa), prostate cancer (PCa), lung cancer and others. However, the effectiveness of PTX is limited by untolerated systemic toxicity, which limits the amount of drug that can be given to kill most if not all cancer cells. This will lad to selective survival of tumor subpopulations with newly acquired drug-resistance. Development of effective delivery systems represents an important strategy to improve the therapeutic index of chemotherapeutic drugs. Abraxane(R) is a human albumin-stabilized nanoformulation of PTX that has been approved for clinical use and demonstrated improvements in both toxicity and efficacy of PTX therapy. However, the size of these particles (~130 nm) is not sufficiently small to achieve effective penetration into poorly vascularized tumor tissues. Micelles-based formulations can effectively deliver drugs to tumors due to their small sizes and various types of polymeric systems have been developed. Most of the polymeric systems use "inert" excipients that lack therapeutic activity. The presence of large amounts of carrier materials not only adds to the cost but also imposes additional safety issue. We have developed a PEG-derivatized embelin- based delivery system that simultaneously enhances targeted delivery and sensitizes the cancer cells to PTX via targeting X-linked inhibitor of apoptosis protein (XIAP). PTX formulated in our novel system shows superior maximal tolerated dose (MTD, 100~120 PTX mg/kg) and antitumor activity over Taxol, a clinically used PTX formulation. This application is focused on improving the delivery system through systematic study on structure-activity relationship (SAR). Their efficiency in synergistic action with PTX is then examined both in vitro and in vivo. Finally, the mechanism of action will be investigated. BCa will be used as a model system to address these issues. Four specific aims will be pursued to achieve our goals: Aim 1 will define the optimal structure of PEG-embelin conjugates through systematic SAR study; Aim 2 will study the mechanism by which PEG-embelin synergizes with co-delivered drug in antitumor activity; Aim 3 will define the efficiency of in vivo tumor targeting and pharmacokinetics in a mouse model of human BCa; Aim 4 will evaluate the synergistic antitumor activity of PEG-embelin-targeted PTX in a mouse model of human BCa xenograft. Completion of the proposed studies in this proposal is likely to lead to the development of a new strategy of targeted combination therapy for the treatment of various types of cancers including BCa.

描述（申请人提供）：紫杉醇（PTX）是治疗多种癌症的一线化疗药物，包括乳腺癌（BCa）、前列腺癌（PCa）、肺癌等。然而，PTX 的有效性受到无法耐受的全身毒性的限制，这限制了杀死大多数（如果不是全部）癌细胞的药物量。这将导致具有新获得的耐药性的肿瘤亚群的选择性存活。开发有效的递送系统是提高化疗药物治疗指数的重要策略。 Abraxane(R) 是一种人白蛋白稳定的 PTX 纳米制剂，已被批准用于临床，并证明可以改善 PTX 疗法的毒性和疗效。然而，这些颗粒的尺寸（~130 nm）还不够小，不足以有效渗透到血管化不良的肿瘤组织中。基于胶束的制剂由于其尺寸小并且已开发出各种类型的聚合物系统，因此可以有效地将药物递送至肿瘤。大多数聚合物系统使用缺乏治疗活性的“惰性”赋形剂。大量载体材料的存在不仅增加了成本，而且还带来了额外的安全问题。我们开发了一种基于 PEG 衍生的 Embelin 的递送系统，该系统通过靶向 X 连锁凋亡蛋白抑制剂 (XIAP)，同时增强靶向递送并提高癌细胞对 PTX 的敏感性。在我们的新系统中配制的 PTX 显示出优于临床使用的 PTX 制剂紫杉醇的最大耐受剂量（MTD，100~120 PTX mg/kg）和抗肿瘤活性。该应用的重点是通过对构效关系（SAR）的系统研究来改进递送系统。然后在体外和体内检查它们与 PTX 协同作用的效率。最后，将研究其作用机制。 BCa 将用作解决这些问题的模型系统。为了实现我们的目标，我们将追求四个具体目标： 目标 1 将通过系统的 SAR 研究确定 PEG-embelin 缀合物的最佳结构；目标2将研究PEG-embelin与共递送药物协同抗肿瘤活性的机制；目标 3 将定义人 BCa 小鼠模型中体内肿瘤靶向和药代动力学的效率；目标 4 将评估 PEG-embelin 靶向的 PTX 在人 BCa 异种移植小鼠模型中的协同抗肿瘤活性。完成该提案中提出的研究可能会导致开发出一种新的靶向联合治疗策略，用于治疗包括 BCa 在内的各种类型的癌症。