optimized Human Apyrase for Bone Cancer Pain Treatment

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著的骨转移能力。三分之二的转移性骨癌患者会经历剧烈疼痛，通常描述为性质迟钝，表现恒定，强度随时间逐渐增加。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。非甾体类抗炎药（NSAID）和阿片类药物是最常用的镇痛药，但受到严重不良副作用的限制，如胃出血和神经精神症状。APT 102是CD 39家族的一种专有的、优化的人腺苷三磷酸双磷酸酶。APT 102选择性地将过量的促炎性和致痛性ATP和促转移性ADP清除为AMP，从而减轻血管炎症、预防转移和减轻疼痛。无处不在的CD 73进一步将AMP代谢为腺苷，腺苷已被证明可减轻人类的神经性疼痛。因此，APT 102的镇痛作用来自ATP的消除和腺苷的产生。在拟议的研究中，我们将评估溶骨性骨癌疼痛模型中APT 102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，并密切反映了人类状况。我们还将在健康大鼠的旋转棒和功能观察组合（FOB）试验中确定APT 102的潜在副作用。长期目标是开发APT 102作为一种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，而没有显著的副作用或成瘾性。

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.