optimized Human Apyrase for Bone Cancer Pain Treatment

用于骨癌疼痛治疗的优化人腺苷三磷酸双磷酸酶

• 批准号: 8589871
• 负责人: RIDONG CHEN
• 金额: $ 28.83万
• 依托单位: APT THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-09 至 2014-09-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8589871
• 关键词: ATP Receptors; Adenosine; Adjuvant; Adverse effects; Affect; American; American Cancer Society; Analgesics; Animals; Apyrase; Arthralgia; Aspirin; Attenuated; Behavior; Behavioral; Biological Assay; Blood Vessels; Bone Density; Breast Cancer Model; Cancer Detection; Cancer Patient; Cause of Death; Cell Line; Chinese Hamster Ovary Cell; Clinical Trials; Data; Disease; Dose; Endotoxins; Exhibits; Family; Fatty acid glycerol esters; Functional disorder; Future; Goals; Hemorrhage; Hormones; Human; Incidence; Inflammation; Inflammatory; Injection of therapeutic agent; Life Expectancy; Malignant Bone Neoplasm; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mammary gland; Metastatic Neoplasm to the Bone; Modeling; Mus; Neoplasm Metastasis; Non-Steroidal Anti-Inflammatory Agents; Opioid; Osteolytic; P2X-receptor; Pain; Patients; Peripheral; Persistent pain; Pharmacologic Substance; Phase; Principal Investigator; Production; Prostate carcinoma; Proteins; Quality of life; Rat-1; Rattus; Refractory; Regimen; Rheumatoid Arthritis; Route; Site; Stomach; Suramin; Symptoms; Therapeutic; Therapeutic Index; Time; Tissues; United States; Work; addiction; bone; cancer pain; cancer therapy; experience; extracellular; functional status; improved; malignant breast neoplasm; mechanical allodynia; melanoma; neuropsychiatry; novel strategies; pain behavior; painful neuropathy; preclinical safety; prevent; programs; public health relevance; response; tumor; vascular inflammation

DESCRIPTION (provided by applicant): Bone metastasis is common in patients with advanced breast, prostate, and lung cancers as these tumors have a remarkable ability to metastasize to bone. Two-thirds of patients with metastatic bone cancer experience severe pain which is usually described as dull in character, constant in presentation, and gradually increasing in intensity with time. Bone cancer pain is one of the most difficult of all persistent pains to control because the metastases are generally not limited to a single site and bone cancer pain is associated with unique pathophysiology. Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are the most commonly used an- algesics, but are limited by significant adverse side effects, such as gastric bleeding and neuropsychiatric symptoms. APT102 is a proprietary, optimized human apyrase of the CD39 family. APT102 selectively scav- enges excess pro-inflammatory and algogenic ATP and pro-metastatic ADP to AMP, thereby attenuating vas- cular inflammation, preventing metastasis, and reducing pain. Ubiquitous CD73 further metabolizes AMP to adenosine, which has been shown to reduce neuropathic pain in humans. Hence, the analgesic effect of APT102 results both from the elimination of ATP and from the production of adenosine. In the proposed studies, we will evaluate the dose-response of APT102 in a model of osteolytic bone cancer pain. This model is driven by in- tra-tibial injections of syngeneic MRMT-1 rat mammary gland carcinoma cells and closely mirrors the human condition. We also will determine the potential side effects of APT102 in the rotarod and Functional Observa- tional Battery (FOB) assays in healthy rats. The long-term goal is to develop APT102 as a safe and effective analgesic therapy. Weekly or bi-weekly dosing will provide sustained pain relief for bone cancer pain patients without significant side effects or addiction.

描述（由申请人提供）：骨转移在晚期乳腺癌、前列腺癌和肺癌患者中很常见，因为这些肿瘤具有显着的骨转移能力。三分之二的转移性骨癌患者会经历剧烈疼痛，这种疼痛通常被描述为性质迟钝、持续存在、并随着时间的推移逐渐加剧。骨癌疼痛是所有持续性疼痛中最难控制的疼痛之一，因为转移通常不限于单个部位，并且骨癌疼痛与独特的病理生理学相关。非甾体抗炎药（NSAID）和阿片类药物是最常用的镇痛药，但其副作用有限，例如胃出血和神经​​精神症状。 APT102 是 CD39 家族的专有、优化的人腺苷三磷酸双磷酸酶。 APT102选择性地清除过量的促炎和致痛的ATP和促转移的ADP，转化为AMP，从而减轻血管炎症、预防转移和减轻疼痛。无处不在的 CD73 进一步将 AMP 代谢为腺苷，这已被证明可以减轻人类的神经性疼痛。因此，APT102 的镇痛作用既来自 ATP 的消除，又来自腺苷的产生。在拟议的研究中，我们将评估 APT102 在溶骨性骨癌疼痛模型中的剂量反应。该模型由胫骨内注射同基因 MRMT-1 大鼠乳腺癌细胞驱动，与人类状况密切相关。我们还将确定 APT102 在健康大鼠的旋转棒和功能观察电池 (FOB) 测定中的潜在副作用。长期目标是将APT102开发为安全有效的镇痛疗法。每周或每两周给药将为骨癌疼痛患者提供持续的疼痛缓解，而不会产生明显的副作用或成瘾。