Cathepsin Inhibitors for Treatment of Breast Cancer Induced Bone Pain

描述（由申请人提供）：世界卫生组织估计，到2020年，全球乳腺癌妇女人数将增加到1500万，其中相当一部分患者处于疾病的晚期。乳腺癌是美国女性最常见的恶性肿瘤，每年有近20万女性被诊断出乳腺癌。美国国立卫生研究院估计，2006年美国癌症的总成本为2063亿美元，其中直接医疗成本为782亿美元。乳腺癌通常转移到骨，导致剧痛、骨重建和最终骨折，导致失能性疼痛和有限或完全丧失活动性。最近对癌症患者的一项研究表明，癌症疼痛的治疗选择存在显着和严重的缺陷，少数患者的发病率要高得多。报告还强调了癌症晚期患者生活质量的重要性，以及对周围家庭和医生的影响。不幸的是，目前癌症引起的骨痛的治疗方法会导致不必要的副作用，甚至会促进骨骼的进一步恶化和超敏反应。本申请通过研究新的组织蛋白酶抑制剂VBY-825（专利WO 2006/102 243）在减轻乳腺癌诱导的骨痛和骨吸收而不导致当前镇痛疗法所见的不希望的副作用方面解决了这种未满足的需求。广泛应用于骨癌转移和来自其他类型肿瘤的相关疼痛的潜力对于这种潜在的治疗是重要的。组织蛋白酶（11种半胱氨酸蛋白酶亚型）包括组织蛋白酶B、S和K，这三种亚型被认为与骨癌疼痛有关。组织蛋白酶B参与癌症转移，启动细胞外基质和基底膜的连接屏障的破坏，从而允许癌细胞通过进入血流侵入新的组织和器官部位。组织蛋白酶K选择性地在破骨细胞中表达，并且在破骨细胞介导的骨吸收中是必需的。重要的是，在骨癌中，组织蛋白酶K也可能参与溶骨性病变的形成。组织蛋白酶S最近与伤害感受有关。部分结扎大鼠左侧坐骨神经（PNL），脊髓背角组织蛋白酶S的表达增加。组织蛋白酶S抑制剂在该模型和许多涉及组织蛋白酶S的神经性疼痛模型中具有镇痛功效，作为神经性疼痛和炎性疼痛中镇痛功效的重要新靶点。Virobay Inc.已经开发了K/S/B（CatK，Ki = 2.3 nM）（CatS，Ki = 130 pM）和（CatB，Ki = 330 pM）的光谱选择性组织蛋白酶抑制剂，用作肿瘤学中的潜在治疗剂，其在抑制 骨癌疼痛在此，我们提出，光谱选择性组织蛋白酶抑制剂将导致乳腺诱导的骨癌疼痛的鼠模型中的自发性和诱发性疼痛行为显著减少，同时缺乏当前阿片类镇痛剂疗法所见的不想要的副作用。提出了三个目的，包括在完善的乳腺诱导的骨癌小鼠模型中测试VBY-825在减少疼痛行为（目的1）、骨丢失、临床相关血清标志物和骨矿物质密度测量（目的2）方面的功效，以及VBY-825的药代动力学和药效学，并与目前的吗啡和双膦酸盐唑来膦酸的临床治疗进行比较（目的3）.总之，大量的人类和小鼠乳腺癌表达组织蛋白酶，并且VBY-825（组织蛋白酶K/S/B的光谱选择性抑制剂）的研究可以为许多骨癌患者提供新的治疗，所述骨癌患者遭受疼痛、骨丢失和当前治疗的不希望的副作用，包括几乎所有患者中用于疼痛的非常高剂量的阿片类药物。

DESCRIPTION (provided by applicant): The World Health Organization estimates that the number of women living with breast cancer globally will rise to 15 million by the year 2020 with a significant portion of these patients in advanced stages of the disease. Breast cancer is the most frequent malignant tumor in women in the U.S. with nearly 200,000 women diagnosed each year. The U.S. NIH estimate overall costs of cancer in the U.S. in 2006 to be $206.3 billion with $78.2 billion in direct medical costs. Breast cancer commonly metastasizes to the bone resulting in excruciating pain, bone remodeling and eventual bone fracture contributing to incapacitating pain and limited or total loss of mobility. A recent study in cancer patients demonstrated a significant and severe deficit in treatment options for cancer pain, with a much higher incidence in minority patients. Reports also highlight the importance of patient quality of life in late stages of cancer, as well as the effects on surrounding family and physicians. Unfortunately, current therapies for cancer-induced bone pain result in unwanted side effects and even promote further deterioration of the bone and hypersensitivities. This application addresses this unmet need by investigating the novel cathepsin inhibitor VBY-825 (Patent WO 2006/102 243) in attenuating breast cancer-induced bone pain and bone resorption without resulting in unwanted side effects seen with current analgesic therapies. The potential for broad application to bone cancer metastases and the associated pain derived from other types of tumors is significant for this potential therapeutic. The cathepsins (11 cysteine protease subtypes) include cathepsins B, S, and K, the three subtypes thought to be involved in bone cancer pain. Cathepsin B is involved in cancer metastasis, initiating the breakdown of connective barriers of the extracellular matrix and basement membrane, thereby allowing cancerous cells to invade new tissues and organ sites by entering the bloodstream. Cathepsin K is selectively expressed in osteoclasts and is essential in osteoclast-mediated bone resorption. Importantly in bone cancer, cathepsin K may also be involved in the formation of osteolytic lesions. Cathepsin S has recently become associated with nociception. Rodents with a partial ligation of the left sciatic nerve (PNL), showed increased expression of cathepsin S in the dorsal horn of the spinal cord. Cathepsin S inhibitors have analgesic efficacy in this model and a number of models of neuropathic pain implicating cathepsin S, as a significant new target for analgesic efficacy in neuropathic and inflammatory pain. Virobay Inc. has developed a spectrum-selective cathepsin inhibitor of K/S/B (CatK, Ki=2.3 nM) (CatS, Ki=130pM) and (CatB, Ki=330pM) for use as a potential therapeutic in oncology with specific utility in the inhibition of bone cancer pain. Here we propose that a spectrum- selective cathepsin inhibitor will result in a significant reduction in spontaneous and evoked pain behaviors in a murine model of breast-induced bone cancer pain while lacking the unwanted side effects seen with current opioid analgesic therapies. Three aims are proposed, including testing of the VBY-825 in a well established murine model of breast-induced bone cancer for efficacy in reducing pain behavior (Aim 1), bone loss, clinically relevant serum markers, and bone mineral density measures (Aim 2), and the pharmacokinetics and pharmacodynamics of VBY-825 with comparisons to current clinical treatments of morphine and the bisphosphonate zoledronic acid (Aim 3). In summary, a significant number of human and murine breast cancers express cathepsins and the investigation of VBY-825 (a spectrum-selective inhibitor of cathepsins K/S/B) may offer a novel therapeutic to many bone cancer patients that suffer from pain, bone loss and the unwanted side effects of current therapies including the very high doses of opioids for pain used in almost all patients.