Tumor Tight Junction Opener + Chemotherapy Conjugates to Treat Cancer

肿瘤紧密连接开放剂化疗结合物治疗癌症

• 批准号: 8647718
• 负责人: DARRICK Albert CARTER
• 金额: $ 19.12万
• 依托单位: PAI LIFE SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-23 至 2015-10-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647718
• 关键词: Abraxane; Address; Adverse effects; Animal Model; Antineoplastic Agents; Binding; Biochemical; Cell Line; Chemicals; Clinical; Dose; Doxorubicin; Doxorubicin Hydrochloride Liposome; Drug Formulations; Epithelial; Escherichia coli; Goals; Growth; Human; Immunocompetent; Injection of therapeutic agent; Intercellular Junctions; Liposomal Doxorubicin; Liposomes; Malignant Neoplasms; Malignant neoplasm of ovary; Marketing; Methodology; Modeling; Molecular Weight; Monitor; Mus; Outcome; Ovarian; Paclitaxel; Particulate; Patients; Penetration; Pharmaceutical Preparations; Phase; Property; Proteins; Recombinant Proteins; Regimen; Research; Resistance; Rest; Safety; Solid Neoplasm; Testing; Therapeutic; Therapeutic Effect; Therapeutic Monoclonal Antibodies; Tight Junctions; Time; Transgenic Mice; Treatment Efficacy; cancer therapy; chemotherapeutic agent; chemotherapy; clinical efficacy; crosslink; desmoglein 2; global health; improved; interest; killings; mouse model; neoplastic cell; next generation; nonhuman primate; oncology; pre-clinical; public health relevance; research clinical testing; response; therapeutic protein; therapy development; tumor; tumor microenvironment

Project Summary Tumors survive cancer therapy in part by blocking the entrance and permeation of drugs into the cancer. We have developed a therapeutic, "JO-1", that selectively opens up tumors, which dramatically enhances penetration. This results in markedly increased concentrations of cancer drugs in the tumor, which becomes a "sink", thereby reducing drug levels in the rest of the body. JO-1 may allow doctors to treat patients with cancer drugs at increased doses, which directly correlates with enhanced therapeutic effects. At the same time, it could reduce or eliminate the side effects of cancer therapy and address one of the major needs of the current state-of-the- art: Developing therapies that are both more effective and less toxic. Importantly, JO-1 can be used to improve clinical outcomes with cancer drugs that are already on the market as well as the next generation of cancer drugs. The goal of this proposal is to develop and test a new Targeted / Enhancing Conjugate ("TEC") of a tumor-targeting tight junction opener with a chemotherapeutic agent. The targeting and enhancing construct (1) Will be targeted to tumors (2) Will open the tumor microenvironment (3) Will therefore allow for dramatic levels of drug accumulation (4) Will result in increased killing of tumor cells and improved clinical efficacy We will do this research in two straightforward steps: we will first produce JO-1 / nab-paclitaxel (a chemotherapy drug) conjugates and then we will test the conjugates for enhanced therapeutic efficacy in an animal model of ovarian cancer. If we are successful, we will further move this new type of therapy towards clinical testing in humans.

项目摘要 肿瘤在癌症治疗中存活，部分原因是阻断了药物进入和渗透， 癌症我们已经开发出一种治疗剂“JO-1”，它选择性地打开肿瘤， 大大增强了穿透力。这导致癌症浓度显著增加 药物在肿瘤中，成为一个“水槽”，从而降低药物水平在身体的其余部分。 JO-1可能允许医生以增加剂量的癌症药物治疗患者， 与增强的治疗效果相关。与此同时，它可以减少或消除 癌症治疗的副作用，并解决当前国家的主要需求之一， art：开发更有效且毒性更小的治疗方法。重要的是，JO-1可以 用于改善已经上市的癌症药物的临床结果， 下一代抗癌药物 本提案的目标是开发和测试新的靶向/增强结合物（“TEC”） 肿瘤靶向紧密连接开放剂与化疗剂的组合。其针对性和 增强结构 (1)将针对肿瘤 (2)会打开肿瘤微环境 (3)因此会导致药物大量累积 (4)将导致增加对肿瘤细胞的杀伤并提高临床疗效 我们将通过两个简单的步骤来进行这项研究：我们将首先生产JO-1 /nab-紫杉醇 （化疗药物）结合物，然后我们将测试结合物的增强 在卵巢癌动物模型中的治疗效果。如果成功，我们将进一步 将这种新型疗法推向人类临床试验。

项目成果

Structure-based Design of JOC-x, a Conjugatable Tumor Tight Junction Opener to Enhance Cancer Therapy.

JOC-x 的基于结构的设计，一种可接合的肿瘤紧密连接开放剂，可增强癌症治疗。

• DOI: 10.1038/s41598-019-42229-3
• 发表时间: 2019
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Pitner,Ragan;Kim,Jiho;Davis-Bergthold,Jenn;Turner,Cheri;Vassal-Stermann,Emilie;Wang,Hongjie;Adams,Jaclyn;Carter,Lauren;Ahlgren,JeffreyA;Fender,Pascal;Lieber,André;Carter,Darrick;Gray,SeanA
• 通讯作者: Gray,SeanA