Selective Delivery of Monomethyl Auristatin Derivatives to Prostate Tumors Using

使用单甲基 Auristatin 衍生物选择性递送至前列腺肿瘤

• 批准号: 8758117
• 负责人: MATTHEW K ROBINSON
• 金额: $ 19.76万
• 依托单位: LEHIGH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-08 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8758117
• 关键词: Acidity; Address; Adverse effects; American; Antibodies; Antigens; Antimitotic Agents; Antineoplastic Agents; Area; Biochemical; Biodistribution; Biological Markers; Cancer Etiology; Castration; Cell Line; Cessation of life; Chemotherapy-Oncologic Procedure; Clinic; Clinical; Cytoplasm; Cytotoxic agent; Data; Development; Disease; Disease Progression; Disease Resistance; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Endosomes; Evaluation; Exhibits; Goals; Half-Life; Heterogeneity; Hypoxia; Image; In Vitro; Lead; Lysosomes; Magnetic Resonance Imaging; Malignant neoplasm of prostate; Maximum Tolerated Dose; Membrane Lipids; Metabolism; Metastatic Neoplasm to the Bone; Modality; Modeling; Molecular; Oncogenic; Outcome; Outcome Study; PC3 cell line; Patients; Peptides; Pharmaceutical Preparations; Preclinical Testing; Process; Prostatic Neoplasms; Proteins; Resistance; Series; Serum; Testing; Therapeutic; Toxic effect; Translating; Treatment Efficacy; Tumor Volume; Validation; Work; base; cancer therapy; castration resistant prostate cancer; cell killing; cytotoxic; cytotoxicity; design; effective therapy; improved; in vivo; killings; men; novel; novel therapeutics; pre-clinical; prostate cancer cell; protein expression; public health relevance; research clinical testing; research study; success; tumor

DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of cancer death in American men. To date, there is no cure for the disease once it has reached a metastatic, castration-resistant state. Therapies that increase survival by several months are considered clinical successes. Alternative approaches to treatment are obviously necessary. The studies outlined in this proposal will address this need by exploiting a novel and underexplored drug delivery vehicle, the pH(Low) Insertion Peptide (pHLIP), for tumor selective delivery of clinically validated cytotoxic monomethyl auristatins (MMAs) in the form of pHLIP-MMA conjugate. Unlike antibody drug conjugates, pHLIP's targeting and payload delivery mechanism relies solely on tumor acidity rather than on any specific antigen. This unique mechanism overcomes the need to escape endosomes or lysosomes and circumvents loss of antigen expression; drawbacks of antibody drug conjugates. Thus, we hypothesize that pHLIP-based drug conjugates will have an enhanced therapeutic window as compared to free drug, providing a mechanism to overcome the hurdle of systemic toxicity and ultimately improve patient outcome over current chemotherapy regimens. A series of experiments have been outlined to specifically address the diverse efforts necessary for each of the steps in the pHLIP-MMA development process. Aim 1 will concentrate on biophysical and biochemical characterization of pHLIP-MMA conjugates to optimize in vitro cytotoxicity efficacy in prostate cancer cell lines. Efforts will focus on cytotoxic agent, linker nd peptide design, and stability as variables for enhancing efficacy. Aim 2 will test the therapeutic efficacy associated with the lead pHLIP-MMA conjugate identified in Aim 1 through biodistribution, pharmacokinetics, maximum tolerated dose, and magnetic resonance imaging of tumor volume studies in orthotopic and bone metastasis models of castration-resistant prostate cancer. Successful completion of the proposed work will result in a lead molecule with sufficient data to warrant additional development along a path to clinical testing.

描述（由申请人提供）：前列腺癌是美国男性癌症死亡的第二大原因。迄今为止，一旦该疾病达到转移性，cast割状态，尚无治愈方法。将生存增加几个月的疗法视为临床成功。显然需要采用其他治疗方法。该提案中概述的研究将通过利用新型且未充分忽视的药物输送车，pH（低）插入肽（PHLIP），以肿瘤选择性地递送临床验证的经过临床验证的细胞毒性单甲基甲虫（MMA）（MMAS），以Phlip-MmaMaMAMMA偶联物的形式进行。与抗体药物缀合物不同，Phlip的靶向和有效载荷递送机制仅依赖于肿瘤酸度，而不是任何特定的抗原。这种独特的机制克服了逃避内体或溶酶体的需求，并规避了抗原表达的丧失。抗体药物缀合物的缺点。因此，我们假设基于phlip的药物缀合物将具有增强的治疗窗口，与自由药物相比，提供了一种克服全身毒性障碍的机制，并最终改善了患者对当前化学疗法方案的结果。 已经概述了一系列实验，以专门解决Phlip-MMA开发过程中每个步骤所需的各种努力。 AIM 1将集中于Phlip-MMA偶联物的生物物理和生化表征，以优化前列腺癌细胞系中体外细胞毒性疗效。努力将重点放在细胞毒性剂，接头ND肽设计和稳定性作为增强功效的变量上。 AIM 2将测试与AIM 1中通过生物分布，药代动力学，最大耐受剂量以及肿瘤体积研究的磁共振成像在AIM 1中鉴定的铅Phlip-MMA结合物相关的治疗疗效。 成功完成拟议的工作将导致铅分子具有足够的数据，以便沿着临床测试的途径进行其他开发。