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

基本信息

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
项目类别：
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

项目摘要

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亡原因。许多认可的癌症药物，例如硼替佐米（Velcade），是杀死正常细胞和肿瘤细胞的细胞毒性剂。治疗益处取决于肿瘤细胞比正常细胞更敏感，从而可以在相对安全的药物剂量下实现临床反应。但是，对正常组织的损害是不可避免的，并且通常会限制治疗。由于其在多发性骨髓瘤（MM）中的显着疗效，硼替佐米在固体癌症中进行了测试。但是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。由于蛋白酶体在正常和肿瘤细胞中调节细胞生理学，因此硼替佐米会引起许多剂量依赖性副作用，这种副作用被称为外周神经病（PN）的感觉和运动功能障碍，而血小板（血栓细胞减少）的血小板不足是最严重的。可以安全治疗MM患者，因为MM细胞可以通过耐硼替佐米的剂量杀死，尽管并非没有PN的频繁发生率。相比之下，固体癌的肿瘤细胞具有更大的耐药性，PN和血小板减少症可阻止以可接受的安全性给予有效剂量的硼替佐米。 ARI-3996是硼替佐米样细胞毒性剂的亲药版本，旨在更有选择地靶向实体瘤中的蛋白酶体。 ARI-3996对所有细胞均相对无毒，直到肿瘤细胞被酶激活，成纤维细胞激活蛋白（FAP）。由于FAP是在上皮肿瘤中产生的，但通常不在健康组织中产生，因此不应在神经组织或血小板产生血小板的骨髓中激活ARI-3996。因此，ARI-3996应杀死与与硼替佐米相关的PN和血小板减少症的严重PN和血小板减少症。如果成功，ARI-3996可能会与化学疗法相结合以提高当前护理标准。 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以杀死组织培养的肿瘤细胞。现在建议证明，ARI-3996可以在与硼替佐米的全身毒性的动物模型中杀死肿瘤。将选择小鼠模型，其中肿瘤的FAP与人上皮肿瘤中的FAP相当。将确定ARI-3996的剂量反应，以减少肿瘤生长，肿瘤细胞死亡以及减少对肿瘤的血液供应。与硼替佐米相比，将检查小鼠的毒性副作用。对于ARI-3996成为可行的候选药物，必须证明，ARI-3996的治疗产生明显的抗肿瘤作用，其系统性毒性至少比硼替佐米少10倍。公共卫生相关性：bortezomib（Velcade）是多发性骨髓瘤的有效治疗方法，但其作用机理导致周围神经病的剂量限制毒性（DLT）和血小板丧失，从而阻止了常见固体癌症的治疗。 Pro-Drug Ari-3996旨在在健康的器官中保持不活跃，并通过肿瘤相关的酶在肿瘤中释放出肿瘤中的细胞毒性硼替Zomib，称为成纤维细胞激活蛋白（FAP），从而可以减少毒性侧面的固体处理，从而使borte tamors降低毒素的治疗。如果在ARI-3996中显示出在FAP产生FAP产生的上皮癌的小鼠模型中具有硼替佐米等量的抗肿瘤作用，与硼替佐米相比，毒性至少降低了10倍，则将用于辅助研究。