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：
8714288
负责人：
WILLIAM W BACHOVCHIN
金额：
$ 53.48万
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 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8714288
关键词：
Accounting Address Adult Adverse effects Aftercare Albumins Anemia Antineoplastic Agents Back Biological Assay Biopsy Biopsy Specimen Body Weight Bone Marrow Bortezomib Breast Cachexia Cancer Patient Cause of Death Cell Line Cells Chemicals Chemistry Cleaved cell Clinic Clinical Clinical Research Clinical Trials Cytotoxic agent Development Diphtheria Toxin Dose Doxorubicin Drug Kinetics Drug Targeting Drug resistance Embryo Enzymes Epithelial Equilibrium Excision Exhibits Exposure to Fibroblasts Fox Chase Cancer Center Genetic Genotype Goals Half-Life Heart Diseases Human Immune system Immunocompetent Immunodeficient Mouse Immunologic Surveillance Immunosuppression Immunosuppressive Agents Incidence Kidney Lead Learning Life Link Lung Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Marketing Maximum Tolerated Dose Mesenchymal Modeling Modification Mus Mutate Mutation New Agents Non-Malignant Normal tissue morphology Oncogene Proteins Oncogenes Patient Selection Patients Peptides Phase Problem Solving Prodrugs Prostate Proteasome Inhibitor Proteins Relapse Reporting Resistance Risk Safety Sampling Serine Protease Small Business Technology Transfer Research Solid Neoplasm Substrate Specificity T-Lymphocyte Testing Therapeutic Index Tissues Toxic effect Transgenic Mice Tumor Immunity Tumor Tissue Velcade Vitamin B Complex Work Xenograft Model Xenograft procedure adaptive immunity base cancer cell cancer therapy chemotherapeutic agent chemotherapy clinical risk commercialization connective tissue stroma cytotoxic design diphtheria toxin receptor drug candidate fibroblast-activating factor improved in vivo killings melanoma neoplastic cell overexpression preclinical efficacy preclinical safety programs prolyl oligopeptidase public health relevance recombinase tumor tumor growth tumor xenograft

项目摘要

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.

描述（由申请人提供）：癌症是美国心脏病之后的第二大死亡原因。化学疗法是手术切除肿瘤后治疗的主要手段。但是，临床益处与残疾或威胁生命的副作用的平衡通常不确定。癌症的基因分型以鉴定出突变的癌基因，这使得有针对性的治疗时代。靶向促进肿瘤生长的突变蛋白的药物有望改变癌症治疗；但是癌症固有的遗传可塑性限制了可以对治疗做出反应的患者，以及那些这样做的患者通常由于耐药性的发展而复发。该提案描述了旨在杀死肿瘤损害健康组织的前药。前药设计为保持无害，直到它们被酶成纤维细胞激活蛋白（FAP）裂解为止。短肽与细胞毒性分子（杀了肿瘤的弹头）有关，以创建前药，仅当特定肽键通过FAP酶上裂解时，才释放其弹头。 FAP由上皮肿瘤的结缔组织（基质）中的非恶性成纤维细胞表达。因此，前药使肿瘤能够独立于癌细胞的突变状态以细胞毒性为目标。对于ARI-3996，在STTR I期证明了前药的可行性，该ARI-3996将类似Velcade的蛋白酶体抑制剂提供给肿瘤，并用ARI-3099DOX确认，该ARI-3099DOX提供了化学治疗剂阿霉素（DOX）。 ARI-3099DOX和ARI-3996都是有前途的候选毒品。然而，在进行索引研究之前，将需要进一步的STTR II期计划，以：（1）改善体内前药半衰期，（2）评估杀死FAP+细胞可能导致的安全风险在正常组织中发现，（3）通过新的作用机理，前药是否可以缓解肿瘤免疫抑制以激活免疫系统以杀死肿瘤[1]。 Arisaph开发了制造独特的前药所需的化学性质，因为它们被FAP释放出细胞毒性弹头，而不是通过密切相关的酶，脯氨酰内肽酶释放出细胞毒性的弹头，否则它将对患者造成毒性的主要风险，因为它在许多健康的组织中都表现出来。通过简单的活检测定法对肿瘤样本中的FAP活性进行简单的活检测定法，可以通过备份化合物和临床风险来减轻发育风险。 Arisaph的合作者H. Borghaei博士（Fox Chase Cancer Center）开发了一种内源性肺癌模型，用于测试前药的可能免疫学作用。 STTR II期的目的是根据临床前功效和安全性选择最有效的前药候选者，以实现Arisaph在第三阶段中进行的辅助研究。