A FAP-Activated Proteasome Inhibitor for Killing Solid Tumors

描述(申请人提供)：在美国，癌症是仅次于心脏病的第二大死因。化疗是手术切除肿瘤后的主要治疗方法；但临床益处与致残或危及生命的副作用之间的平衡往往是不确定的。对癌症进行基因分型以识别突变的癌基因，使靶向治疗时代成为可能。针对驱动肿瘤生长的突变蛋白的药物有望给癌症治疗带来革命性的变化；但癌症固有的遗传可塑性限制了 那些对治疗有反应的患者和那些对治疗有反应的患者，往往会因为产生抗药性而复发。该提案描述了旨在以减少对健康组织的损害来杀死肿瘤的前药。这些前药物被设计为在被成纤维细胞激活蛋白(FAP)酶切割之前保持无害。短肽与细胞毒分子(杀瘤弹头)相连，产生前药物，当特定的肽键被FAP酶切时才释放弹头。FAP是由上皮性肿瘤结缔组织(间质)中的非恶性成纤维细胞表达的；因此，前药使肿瘤能够被细胞毒剂靶向，而不依赖于癌细胞的突变状态。ARI-3996的前药可行性在STTRI-3996阶段得到证实，ARI-3996向肿瘤输送VELCADE样蛋白酶体抑制剂，并通过ARI-3099DOX确认，ARI-3099DOX输送化疗药物阿霉素(DOX)。ARI-3099DOX和ARI-3996都是很有前途的候选药物。然而，在继续进行支持IND的研究之前，计划在STTR第二阶段进行的进一步工作将需要：(1)改善前药在体内的半衰期，(2) 评估杀死FAP细胞可能导致的潜在安全风险 (3)了解前药物是否可以通过一种新的作用机制解除肿瘤免疫抑制，从而激活免疫系统以杀死肿瘤[1]。Arisaph已经开发出制造前药所需的化学物质，这些药物是独特的，因为它们被FAP裂解以释放细胞毒弹头，但不是由密切相关的酶-脯氨酰内肽酶-释放，否则将对患者构成重大毒性风险，因为它在许多健康组织中表达。通过补充化合物的能力和临床风险，通过对肿瘤样本中FAP活性的简单活组织检查来选择患者，可以减轻发育风险。Arisaph的合作者H.Borghaei博士(Fox Chase癌症中心)已经开发出一种内源性肺癌模型，用于测试前体药物可能的免疫学效果。STTR第二阶段的目标是根据临床前的有效性和安全性，为Arisaph将在第三阶段进行的IND使能研究选择最有效的前药物候选者。

DESCRIPTION (provided by applicant): Cancer is the second leading cause of death after heart disease in the US. Chemotherapy is a mainstay of treatment after surgical removal of tumors; but the balance of clinical benefit versus disabling or life- threatening side effects is often uncertain. Genotyping of cancers to identify mutated oncogenes has enabled an era of targeted therapy. Drugs targeting the mutated proteins that drive tumor growth promised to revolutionize cancer treatment; but the genetic plasticity inherent in cancer limits the numbers of patients who can respond to treatment, and those that do, often relapse due to development of drug resistance. This proposal describes prodrugs intended to kill tumors with reduced damage to healthy tissues. The prodrugs are designed to remain harmless until they are cleaved by the enzyme fibroblast activation protein (FAP). Short peptides are linked to cytotoxic molecules (tumor-killing warheads) to create prodrugs that only release their warheads when a specific peptide bond is cleaved enzymatically by FAP. FAP is expressed by nonmalignant fibroblasts in the connective tissue (stroma) of epithelial tumors; therefore, prodrugs enable tumors to be targeted with cytotoxic agents independently of the mutational status of the cancer cell. Prodrug feasibility was demonstrated in STTR Phase I for ARI-3996, which delivers a Velcade-like proteasome inhibitor to the tumor, and confirmed with ARI-3099DOX, which delivers the chemotherapeutic agent doxorubicin (DOX). ARI-3099DOX and ARI-3996 are both promising drug candidates. Before proceeding to IND-enabling studies, however, further work, which is planned for STTR Phase II, will be required in order to: (1) improve prodrug half-life in vivo, (2) evaluate the possible safety risk that might result from killing FAP+ cells that have recently been discovered in normal tissues, and (3) understand whether, by a new mechanism of action, prodrugs can relieve tumoral immune suppression to activate the immune system to kill tumors [1]. Arisaph has developed chemistry required to make prodrugs that are unique in that they are cleaved to release cytotoxic warheads by FAP, but not by a closely related enzyme, prolyl endopeptidase, which would otherwise present a major risk of toxicity to the patient because it is expressed in many healthy tissues. Developmental risk is mitigated by ability to make back up compounds, and clinical risk, by patient selection with a simple biopsy assay for FAP activity in tumor samples. Arisaph's collaborator, Dr. H. Borghaei (Fox Chase Cancer Center), has developed a model of endogenous lung cancer for testing the possible immunological effects of prodrugs. The goal of STTR Phase II is to select the most efficacious prodrug candidate, based on preclinical efficacy and safety, for IND-enabling studies that will be conducted by Arisaph in Phase III.