Cathepsin Inhibitors for Treatment of Breast Cancer Induced Bone Pain

描述(申请人提供)：世界卫生组织估计，到2020年，全球患有乳腺癌的妇女人数将增加到1500万，其中很大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20万名女性确诊。美国国立卫生研究院估计，2006年美国癌症的总成本为2,063亿美元，其中直接医疗成本为782亿美元。乳腺癌通常转移到骨骼，导致极度疼痛、骨骼重塑和最终骨折，导致丧失能力的疼痛和有限或完全丧失活动能力。最近对癌症患者的一项研究表明，癌症疼痛的治疗选择严重不足，少数族裔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，目前治疗癌症引起的骨痛会导致不良的副作用，甚至会导致骨骼进一步恶化和过敏。本申请通过研究新型组织蛋白酶抑制剂VBY-825(专利WO 2006/102 243)来解决这一未得到满足的需求，该药物可以减轻乳腺癌引起的骨痛和骨吸收，而不会导致当前止痛治疗中出现的不希望看到的副作用。对于骨转移癌和其他类型肿瘤引起的相关疼痛的广泛应用的潜力对这种潜在的治疗方法具有重要意义。这些组织蛋白(11种半胱氨酸蛋白酶亚型)包括组织蛋白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参与肿瘤转移，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在破骨细胞中选择性表达，在破骨细胞介导的骨吸收中起重要作用。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最近与伤害性感受联系在一起。部分结扎左侧坐骨神经的大鼠脊髓背角组织蛋白酶S表达增加。组织蛋白酶S抑制剂在该模型和多种神经病理性疼痛模型中均有镇痛作用，组织蛋白酶S可作为治疗神经病理性疼痛和炎症性疼痛的重要新靶点。Virobay Inc.已经开发出一种K/S/B(CatK，Ki=2.3nM)(CATS，Ki=130 pm)和(CatB，Ki=330 pm)的组织蛋白酶抑制剂，作为一种潜在的肿瘤学治疗药物，具有特殊的抑制作用 骨癌疼痛。在这里，我们提出，在乳腺癌诱导的骨癌疼痛的小鼠模型中，光谱选择性组织蛋白酶抑制剂将导致自发和诱发性疼痛行为的显着减少，同时没有目前阿片类止痛疗法所看到的不良副作用。提出了三个目标，包括在已建立的乳腺癌诱发骨癌小鼠模型中测试VBY-825在减少疼痛行为(目标1)、骨丢失、临床相关血清标记物和骨密度测量方面的有效性(目标2)，以及VBY-825的药代动力学和药效学，并与目前临床治疗的吗啡和双膦酸唑来膦酸(目标3)进行比较。综上所述，大量人类和小鼠乳腺癌表达组织蛋白，而VBY-825(组织蛋白K/S/B的选择性抑制剂)的研究可能为许多遭受疼痛、骨丢失和现有治疗方法不良副作用的骨癌患者提供一种新的治疗方法，其中包括几乎所有患者都使用非常大剂量的阿片类药物止痛。

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.