A FAP-Activated Proteasome Inhibitor for Killing Solid Tumors

描述（由申请人提供）：癌症是美国第二大死因。许多被批准的抗癌药物，如硼替佐米（Velcade），都是细胞毒性药物，既能杀死正常细胞，也能杀死肿瘤细胞。治疗效果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，对正常组织的损伤是不可避免的，往往限制了治疗。由于其对多发性骨髓瘤（MM）的显著疗效，硼替佐米已经在实体癌中进行了测试；但它通常未能产生临床反应。硼替佐米抑制一种叫做蛋白酶体的细胞内蛋白质复合物。由于蛋白酶体调节正常细胞和肿瘤细胞的细胞生理，硼替佐米引起许多剂量依赖性副作用，其中感觉和运动功能障碍称为周围神经病变（PN）和血小板缺乏（血小板减少症）是最严重的。MM患者可以安全治疗，因为在耐受剂量的硼替佐米可以杀死MM细胞，尽管并非没有频繁的PN发生率。相比之下，实体癌的肿瘤细胞更具耐药性，PN和血小板减少症使硼替佐米的有效剂量无法达到可接受的安全性。ARI-3996是一种硼替佐米样细胞毒制剂的前药版本，旨在更有选择性地靶向实体肿瘤中的蛋白酶体。ARI-3996对所有细胞都是相对无毒的，在被成纤维细胞激活蛋白（FAP）激活之前，它不能杀死肿瘤细胞。由于FAP在上皮肿瘤中产生，但通常不在健康组织中产生，因此ARI-3996不应在产生血小板的神经组织或骨髓中被激活。因此，ARI-3996应该能够杀死产生fap的肿瘤，而与硼替佐米相关的PN和血小板减少症的严重程度较低。如果成功，ARI-3996可能会与化疗联合使用，以提高目前的治疗标准。FAP已被证明可以特异性激活ARI-3996并释放硼替佐米样蛋白酶体抑制剂来杀死组织培养中的肿瘤细胞。现在有人提出要证明ARI-3996可以在上皮癌动物模型中杀死肿瘤，但其全身毒性低于硼替佐米。将选择一种小鼠模型，其中肿瘤产生的FAP量相当于人类上皮肿瘤中的FAP量。ARI-3996的剂量反应将被确定为肿瘤生长减少、肿瘤细胞死亡和肿瘤血供减少。与硼替佐米相比，将检查小鼠的毒副作用。为了使ARI-3996成为可行的候选药物，必须证明ARI-3996治疗产生显著的抗肿瘤作用，且全身毒性至少比硼替佐米低10倍。

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.