A FAP-Activated Proteasome Inhibitor for Killing Solid Tumors

描述(申请人提供)：癌症是美国第二大死因。许多被批准的抗癌药物，如Bortezomib(VELCADE)，都是细胞毒剂，既能杀死正常细胞，也能杀死肿瘤细胞。治疗的益处取决于肿瘤细胞比正常细胞更敏感，从而允许在相对安全的药物剂量下实现临床反应；然而，对正常组织的损害是不可避免的，往往限制了治疗。由于其对多发性骨髓瘤(MM)的显著疗效，Bortezomib已被用于实体癌症的测试；但它通常无法产生临床反应。Bortezomib抑制一种称为蛋白酶体的细胞内蛋白质复合体。由于蛋白酶体调节正常细胞和肿瘤细胞的细胞生理，Bortezomib会引起许多剂量依赖的副作用，其中最严重的是感觉和运动功能障碍，称为周围神经病(PN)和血小板缺乏(血小板减少症)。多发性骨髓瘤患者可以得到安全的治疗，因为波特佐米可以在耐受的剂量下杀死多发性骨髓瘤细胞，尽管不是在没有PN频繁发生的情况下。相比之下，实体癌的肿瘤细胞更具抗药性，PN和血小板减少阻止了有效剂量的Bortezomib的使用，而且安全性可以接受。ARI-3996是一种类似于Bortezomib的细胞毒剂的亲药物版本，旨在更有选择性地针对实体肿瘤中的蛋白酶体。ARI-3996对所有细胞相对无毒，在被成纤维细胞激活蛋白(FAP)酶激活之前不能杀死肿瘤细胞。由于FAP在上皮性肿瘤中产生，但通常不在健康组织中产生，因此ARI-3996不应在神经组织或产生血小板的骨髓中激活。因此，ARI-3996应能以比波特佐米更轻的PN和血小板减少来杀死产生FAP的肿瘤。如果成功，ARI-3996可能会与化疗相结合，以改善目前的护理标准。FAP已被证明能特异性激活ARI-3996，并释放Bortezomib样蛋白酶体抑制剂，在组织培养中杀死肿瘤细胞。现在有人建议证明ARI-3996可以在上皮性癌症的动物模型中杀死肿瘤，而全身毒性比Bortezomib要小。将选择一种小鼠模型，在该模型中，肿瘤产生与人类上皮性肿瘤相同数量的FAP。ARI-3996的剂量反应将被确定为减少肿瘤生长、肿瘤细胞死亡和减少肿瘤的血液供应。与波特佐米相比，将对小鼠进行毒副作用检查。ARI-3996要成为可行的候选药物，关键是要证明ARI-3996治疗产生显著的抗肿瘤效果，并且全身毒性至少比Bortezomib少10倍。 公共卫生相关性：Bortezomib(VELCADE)是治疗多发性骨髓瘤的有效药物，但其作用机制会导致周围神经病变和血小板丢失的剂量限制性毒性(DLTS)，从而阻止常见实体癌症的治疗。前药ARI-3996在健康器官中保持不活跃，并被激活，通过一种名为成纤维细胞激活蛋白(FAP)的肿瘤相关酶在肿瘤中释放出一种细胞毒性的Bortezomib样弹头，从而减少阻碍Bortezomib安全治疗实体肿瘤的毒副作用。如果ARI-3996在产生FAP的上皮性癌症的小鼠模型中被证明具有与Bortezomib同等的抗肿瘤作用，并且毒性至少比Bortezomib减少10倍，则将申请Ind支持研究的第二阶段资金。

DESCRIPTION (provided by applicant): Cancer is America's second leading cause of death. Many approved cancer drugs, such as bortezomib (Velcade), are cytotoxic agents that kill normal cells as well as tumor cells. Therapeutic benefit depends on tumor cells being more sensitive than normal cells, thereby allowing clinical responses to be achieved at relatively safe drug doses; however, damage to normal tissues is unavoidable and often limits treatment. Due to its remarkable efficacy in multiple myeloma (MM), bortezomib has been tested in solid cancers; but it has generally failed to produce clinical responses. Bortezomib inhibits an intracellular protein complex called the proteasome. Because the proteasome regulates cellular physiology in both normal and tumor cells, bortezomib causes many dose-dependent side effects of which sensory and motor dysfunction called peripheral neuropathy (PN) and deficiency in platelets (thrombocytopenia) are the most severe. MM patients can be treated safely, because MM cells can be killed by bortezomib at doses that are tolerated, albeit not without frequent incidence of PN. In contrast, tumor cells of solid cancers are more resistant, and PN and thrombocytopenia prevent administration of an effective dose of bortezomib with acceptable safety. ARI-3996 is a pro-drug version of a bortezomib-like cytotoxic agent designed to more selectively target the proteasome in solid tumors. ARI-3996 is relatively non-toxic to all cells and cannot kill tumor cells until it is activated by the enzyme, fibroblast activation protein (FAP). Because FAP is produced in epithelial tumors but not usually in healthy tissues, ARI-3996 should not be activated in nervous tissue or in bone marrow where platelets are generated. Therefore, ARI-3996 should kill FAP-producing tumors with less severe PN and thrombocytopenia than that associated with bortezomib. If successful, ARI-3996 might be combined with chemotherapy to improve the current standards of care. FAP has been shown to specifically activate ARI-3996 and unleash the bortezomib-like proteasome inhibitor to kill tumor cells in tissue culture. It is now proposed to demonstrate that ARI-3996 can kill tumors in an animal model of epithelial cancer with less systemic toxicity than bortezomib. A mouse model will be selected in which the tumor produces FAP in amounts equivalent to those in human epithelial tumors. The dose-response of ARI-3996 will be determined for reduced tumor growth, death of tumor cells, and reduced blood supply to the tumor. Mice will be examined for toxic side effects in comparison to bortezomib. For ARI-3996 to be a viable drug candidate, it will be essential to demonstrate that treatment with ARI-3996 produces significant antitumor effects with at least 10-fold less systemic toxicity than bortezomib. PUBLIC HEALTH RELEVANCE: Bortezomib (Velcade) is an effective treatment for multiple myeloma, but its mechanism of action results in dose-limiting toxicities (DLTs) of peripheral neuropathy and loss of platelets, which prevent treatment of common solid cancers. The pro-drug, ARI-3996, is designed to remain inactive in healthy organs and to be activated to unleash a cytotoxic bortezomib-like warhead in tumors by the tumor-associated enzyme called fibroblast activation protein (FAP), thereby reducing the toxic side effects that prevent safe treatment of solid tumors with bortezomib. If ARI-3996 is shown to have a bortezomib-equivalent antitumor effect in a mouse model of FAP-producing epithelial cancer with at least a 10-fold reduction in toxicity compared to bortezomib, Phase II funding for IND-enabling studies will be applied for.