In Vivo Study of of Chemokine Antagonists for Cancer

描述(申请人提供)：转移性乳腺癌导致患者死亡。我们的研究重点是开发一种新的治疗平台来阻止转移性乳腺癌的进展。有相当多的证据表明趋化因子参与了转移性肿瘤细胞疾病的扩散。我们已经发现了针对肿瘤细胞中CX3CR1的新型小分子CX3CR1拮抗剂，并表明这种趋化因子受体参与了肿瘤的转移。这项建议旨在评估趋化因子介导的传播作为一种新的治疗方法来阻止循环中的肿瘤细胞归巢、阻止和外溢到骨髓。我们已经在Fractalkine基因敲除动物中证明了靶向概念，并在转移动物模型中使用针对癌细胞上表达的CX3CR1的中和抗体进行治疗，显示向骨骼播散的肿瘤细胞显著减少。靶向炎症性趋化因子，如Fractalkine，而不是稳态趋化因子，预计将提供一种安全的作用机制。CX3CR1和Fractalkine基因敲除动物都是存活的，与野生型动物相比看起来是正常的，这表明CX3CR1拮抗将是一种相对良性的干预。这种方法将提供针对一个新的分子靶点--趋化因子受体CX3CR1的非细胞毒性药物，以阻止转移性乳腺癌的进展。靶点CX3CR1在恶性组织和高转移肿瘤细胞上过度表达，包括那些与炎症性乳腺癌(IBC)有关的肿瘤细胞。IBC是一种侵袭性很强的转移性疾病，需要新的治疗方法。除了IBC之外，延缓或阻止转移的药物的成功开发预计将具有广泛的有益用途。我们将开发针对高转移肿瘤细胞的专有小分子CX3CR1拮抗剂。CX3CR1中和性单抗和药物结合物可能是后续产品。这项建议的具体目标是：目标1：扩大JMS-17-2的合成规模，以便在我们的体内模型中进行初步评估，并优化先导化合物JMS-16-7和JMS-17-2，以提高选择性和类药物性能，如：水溶性、血浆和肝脏微体稳定性以及微体固有清除性。目的：通过在小鼠体内的药代动力学测定，确定我们最好的CX3CR1拮抗剂在小鼠体内的药代动力学特性，并在我们的转移动物模型中测试这一候选药物。

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.