A FAP-Activated Proteasome Inhibitor for Killing Solid Tumors

描述（由申请人提供）：癌症是美国的第二大死因。许多批准的癌症药物，如硼替佐米（万珂），是细胞毒性药物，杀死正常细胞以及肿瘤细胞。治疗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，对正常组织的损伤是不可避免的，并且通常限制治疗。由于其在多发性骨髓瘤（MM）中的显著疗效，硼替佐米已在实体癌中进行了测试;但它通常未能产生临床反应。硼替佐米抑制一种称为蛋白酶体的细胞内蛋白复合物。由于蛋白酶体调节正常细胞和肿瘤细胞的细胞生理学，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）和血小板缺乏症（血小板减少症）是最严重的。MM患者可以安全地治疗，因为MM细胞可以在耐受剂量下被硼替佐米杀死，尽管并非没有PN的频繁发生。相比之下，实体癌的肿瘤细胞更具抗性，并且PN和血小板减少症阻止了具有可接受安全性的有效剂量的硼替佐米的施用。ARI-3996是硼替佐米样细胞毒性剂的前药版本，旨在更有选择性地靶向实体瘤中的蛋白酶体。ARI-3996对所有细胞相对无毒，并且在被成纤维细胞活化蛋白（FAP）激活之前不能杀死肿瘤细胞。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活化。因此，ARI-3996应该杀死FAP产生的肿瘤，与硼替佐米相关的PN和血小板减少症相比，严重程度较低。如果成功，ARI-3996可能与化疗结合，以提高目前的护理标准。FAP已被证明特异性激活ARI-3996并释放硼替佐米样蛋白酶体抑制剂以杀死组织培养中的肿瘤细胞。现在提出证明ARI-3996可以在上皮癌动物模型中杀死肿瘤，全身毒性低于硼替佐米。将选择小鼠模型，其中肿瘤产生的FAP的量相当于人上皮肿瘤中的FAP的量。将确定ARI-3996的剂量反应，以减少肿瘤生长、肿瘤细胞死亡和减少肿瘤血液供应。将检查小鼠与硼替佐米相比的毒副作用。为了使ARI-3996成为一种可行的候选药物，必须证明ARI-3996治疗产生显著的抗肿瘤作用，全身毒性比硼替佐米低至少10倍。 公共卫生相关性：硼替佐米（万珂）是多发性骨髓瘤的有效治疗方法，但其作用机制导致周围神经病变和血小板丢失的剂量限制性毒性（DLT），这阻碍了常见实体癌的治疗。前药ARI-3996被设计为在健康器官中保持无活性，并被称为成纤维细胞活化蛋白（FAP）的肿瘤相关酶激活以释放肿瘤中的细胞毒性硼替佐米样弹头，从而减少阻止硼替佐米安全治疗实体瘤的毒副作用。如果ARI-3996在产生FAP的上皮癌小鼠模型中显示出与硼替佐米相当的抗肿瘤作用，并且与硼替佐米相比毒性至少降低10倍，则将申请IND使能研究的II期资金。

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.