A FAP-Activated Proteasome Inhibitor for Killing Solid Tumors

FAP 激活的蛋白酶体抑制剂可杀死实体瘤

• 批准号: 8124503
• 负责人: WILLIAM W BACHOVCHIN
• 金额: $ 24.56万
• 依托单位: ARISAPH PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-23 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8124503
• 关键词: A Mouse; Address; Adverse effects; Americas; Animal Model; Antineoplastic Agents; Biological Assay; Biological Markers; Biopsy; Blood Platelets; Bone Marrow; Bortezomib; Breast; C-terminal; Cancer Patient; Carcinoma; Caring; Cause of Death; Cell physiology; Cells; Cessation of life; Cleaved cell; Clinical; Clinical Research; Clinical Trials; Colon; Cytotoxic agent; Development; Dose; Dose-Limiting; Enzymes; Epithelial; Exhibits; Fibroblasts; Functional disorder; Funding; Goals; Human; In Vitro; Incidence; Induction of Apoptosis; Inhibition of Apoptosis; Learning; Malignant Neoplasms; Malignant neoplasm of lung; Maximum Tolerated Dose; Modeling; Motor; Multiple Myeloma; Mus; Nerve Tissue; Normal Cell; Normal tissue morphology; Organ; Pancreas; Pathway interactions; Patients; Peptides; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phase; Plasma; Prodrugs; Proline; Property; Proteasome Inhibition; Proteasome Inhibitor; Relative (related person); Reporting; Resistance; Safety; Sensory; Serine Protease; Side; Signal Transduction; Solid; Solid Neoplasm; Testing; Therapeutic; Therapeutic Index; Thrombocytopenia; Tissues; Toxic effect; Tumor Cell Line; Tumor Tissue; Vascular blood supply; Velcade; Xenograft Model; alanylproline; angiogenesis; antiangiogenesis therapy; base; biological adaptation to stress; cancer therapy; chemotherapy; chymotrypsin inhibitor; common treatment; cytotoxic; cytotoxicity; design; drug candidate; effective therapy; endoplasmic reticulum stress; fibroblast-activating factor; human tissue; improved; in vivo; inhibitor/antagonist; killings; meetings; mouse model; multicatalytic endopeptidase complex; neoplastic cell; pre-clinical; prevent; prognostic; protein complex; prototype; pyrazinoic acid; response; success; tissue culture; tumor; tumor growth; tumor xenograft

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.

描述（由申请人提供）：癌症是美国第二大死因。许多批准的抗癌药物，例如硼替佐米（Velcade），是杀死正常细胞和肿瘤细胞的细胞毒性药物。治疗效果取决于肿瘤细胞比正常细胞更敏感，从而能够以相对安全的药物剂量实现临床反应；然而，对正常组织的损害是不可避免的，并且常常限制治疗。由于硼替佐米对多发性骨髓瘤 (MM) 具有显着疗效，因此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学，硼替佐米会引起许多剂量依赖性副作用，其中最严重的是称为周围神经病（PN）的感觉和运动功能障碍和血小板缺乏（血小板减少症）。 MM 患者可以安全地接受治疗，因为 MM 细胞可以被耐受剂量的硼替佐米杀死，尽管 PN 的发生率并不高。相比之下，实体癌的肿瘤细胞具有更强的抵抗力，并且PN和血小板减少症阻止了以可接受的安全性施用有效剂量的硼替佐米。 ARI-3996 是硼替佐米样细胞毒剂的前药版本，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激活蛋白 (FAP) 酶激活之前无法杀死肿瘤细胞。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 不应在生成血小板的神经组织或骨髓中被激活。因此，ARI-3996 能够杀死产生 FAP 的肿瘤，并且与硼替佐米相关的 PN 和血小板减少症较轻。如果成功，ARI-3996 可能与化疗相结合，以提高当前的护理标准。 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。现在提议证明ARI-3996可以杀死上皮癌动物模型中的肿瘤，且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 量与人类上皮肿瘤中的量相当。 ARI-3996 的剂量反应将通过减少肿瘤生长、肿瘤细胞死亡和减少肿瘤血液供应来确定。将检查小鼠与硼替佐米相比的毒副作用。要使 ARI-3996 成为可行的候选药物，必须证明 ARI-3996 治疗可产生显着的抗肿瘤作用，且全身毒性比硼替佐米至少低 10 倍。 公共健康相关性：硼替佐米 (Velcade) 是治疗多发性骨髓瘤的有效方法，但其作用机制会导致周围神经病变的剂量限制性毒性 (DLT) 和血小板损失，从而阻碍常见实体癌的治疗。该前药 ARI-3996 被设计为在健康器官中保持不活跃状态，并被称为成纤维细胞激活蛋白 (FAP) 的肿瘤相关酶激活，在肿瘤中释放细胞毒性硼替佐米样弹头，从而减少妨碍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，且与硼替佐米相比毒性至少降低10倍，则将申请用于IND研究的II期资助。