In Vivo Study of of Chemokine Antagonists for Cancer

癌症趋化因子拮抗剂的体内研究

• 批准号: 8690420
• 负责人: Joseph M Salvino
• 金额: $ 20.16万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690420
• 关键词: Accounting; Address; Animal Model; Animals; Benign; Biological; Blood; Blood Circulation; Bone Marrow; CX3CL1 gene; Cancer Etiology; Cancer Patient; Cessation of life; Chemotaxis; Chronic; Cytotoxic agent; Development; Disease; Drug Kinetics; Evaluation; Extravasation; Fractalkine; Goals; High Pressure Liquid Chromatography; Homing; Inflammatory; Inhibitory Concentration 50; Intervention; Knock-out; Lead; Liver; Malignant - descriptor; Malignant Neoplasms; Mediating; Metastatic Neoplasm to the Bone; Molecular; Molecular Target; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Patients; Pharmaceutical Preparations; Plasma; Plasma Proteins; Process; Property; Protein Binding; Research; Risk; Route; Series; Skeleton; Testing; Therapeutic; Tissues; Woman; Work; analog; base; cancer cell; chemokine; chemokine receptor; improved; in vivo; in vivo Model; inflammatory breast cancer; killings; malignant breast neoplasm; meetings; mouse model; neoplastic cell; neutralizing antibody; neutralizing monoclonal antibodies; novel; novel strategies; novel therapeutic intervention; novel therapeutics; public health relevance; scale up; small molecule; success; therapeutic target; water solubility

DESCRIPTION (provided by applicant): Metastatic breast cancer kills patients. Our research is focused on developing a novel therapeutic platform to stop the progression of metastatic breast cancer. There is considerable evidence for the involvement of chemokines in metastatic tumor cell disease spreading. We have discovered novel small molecule CX3CR1 antagonists that target CX3CR1 in tumor cells and have shown that this chemokine receptor is involved in metastasis. This proposal aims to evaluate chemokine mediated dissemination as a novel therapeutic approach to halt the homing, arrest, and extravasation of circulating tumor cells to the bone marrow. We have demonstrated target proof of concept in Fractalkine knock-out animals and by treatment with a neutralizing antibody directed toward CX3CR1 expressed on cancer cells in animal models of metastasis by showing a significant decrease in disseminated tumor cells to the skeleton. Targeting an inflammatory chemokine such as Fractalkine as opposed to a homeostatic chemokine is predicted to provide a safe mechanism of action. Both CX3CR1 and Fractalkine knock-out animals are viable and appear normal compared to wild type animals which suggests that CX3CR1 antagonism will be a relatively benign intervention. This approach will provide non- cytotoxic drugs against a novel molecular target, the chemokine receptor CX3CR1, to stop the progression of metastatic breast cancer. The target, CX3CR1, is over expressed in malignant tissue and on highly metastatic tumor cells, including those responsible for inflammatory breast cancer (IBC). IBC is a very aggressive metastatic disease in need of new approaches. In addition to IBC, the successful development of agents which slow or halt metastasis are envisioned to have broad beneficial use. We will develop proprietary small molecule CX3CR1 antagonists which target highly metastatic tumor cells. A CX3CR1 neutralizing monoclonal antibody and drug conjugate approaches are likely as follow-on products. Specific Aims of this proposal are: Aim 1: To scale up the synthesis of JMS-17-2 for preliminary evaluation in our in vivo model, and optimize the lead compounds, JMS-16-7 and JMS-17-2, to improve selectivity and drug-like properties such as; water solubility, plasma and liver microsomal stability, and microsomal intrinsic clearance. Aim 2: To determine the pharmacokinetic properties of our best CX3CR1 antagonist meeting potency and ADME criteria for water solubility, plasma stability, intrinsic clearance, and plasma protein binding by pharmacokinetic determination in the mouse, and to test this candidate in our translational animal models of metastasis.

描述（由申请人提供）：转移性乳腺癌杀死患者。我们的研究重点是开发一个新型的治疗平台，以阻止转移性乳腺癌的发展。有大量证据表明趋化因子参与转移性肿瘤细胞疾病扩散。我们发现了靶向CX3CR1在肿瘤细胞中的新型小分子CX3CR1拮抗剂，并表明该趋化因子受体与转移有关。该提案旨在评估趋化因子介导的传播，作为一种新型的治疗方法，以阻止循环肿瘤细胞向骨髓的归因，停止和渗出。我们已经证明了在分面敲除动物中的概念验证，并通过用针对CX3CR1的中和抗体进行治疗，该抗体在转移动物模型中表达在癌细胞上，通过表现出对骨架的传播肿瘤细胞的显着降低。靶向炎性趋化因子（例如分面碱），而不是稳态趋化因子，可以提供安全的作用机理。与野生型动物相比，CX3CR1和分面敲除动物都是正常的，这表明CX3CR1拮抗作用将是一种相对良性的干预。这种方法将针对一种新的分子靶标，即趋化因子受体CX3CR1提供非细胞毒性药物，以阻止转移性乳腺癌的进展。靶标CX3CR1在恶性组织和高度转移性肿瘤细胞（包括负责炎性乳腺癌（IBC））中过度表达。 IBC是一种非常激进的转移性疾病，需要新方法。除了IBC外，还设想有慢速转移或停止转移的代理的成功开发具有广泛的有益用途。我们将开发专有的小分子CX3CR1拮抗剂，靶向高度转移性肿瘤细胞。 CX3CR1中和单克隆抗体和药物结合方法的方法可能是后续产物。该提案的具体目的是：目标1：在我们的体内模型中扩大JMS-17-2进行初步评估的合成，并优化铅化合物JMS-16-7和JMS-17-2，以提高选择性和类似药物的特性，例如；水溶性，血浆和肝微粒体稳定性以及微粒体内在清除率。目的2：确定我们最佳的CX3CR1拮抗剂的药代动力学特性，满足效力和水溶性标准，用于水溶解度，血浆稳定性，内在清除率和血浆蛋白在小鼠中通过药物的结合，并在我们的转移性转移性动物模型中测试该候选者。