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:
- 金额:$ 53.48万
- 依托单位:
- 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:
- 关键词:AccountingAddressAdultAdverse effectsAftercareAlbuminsAnemiaAntineoplastic AgentsBackBiological AssayBiopsyBiopsy SpecimenBody WeightBone MarrowBortezomibBreastCachexiaCancer PatientCause of DeathCell LineCellsChemicalsChemistryCleaved cellClinicClinicalClinical ResearchClinical TrialsCytotoxic agentDevelopmentDiphtheria ToxinDoseDoxorubicinDrug KineticsDrug TargetingDrug resistanceEmbryoEnzymesEpithelialEquilibriumExcisionExhibitsExposure toFibroblastsFox Chase Cancer CenterGeneticGenotypeGoalsHalf-LifeHeart DiseasesHumanImmune systemImmunocompetentImmunodeficient MouseImmunologic SurveillanceImmunosuppressionImmunosuppressive AgentsIncidenceKidneyLeadLearningLifeLinkLungMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of pancreasMarketingMaximum Tolerated DoseMesenchymalModelingModificationMusMutateMutationNew AgentsNon-MalignantNormal tissue morphologyOncogene ProteinsOncogenesPatient SelectionPatientsPeptidesPhaseProblem SolvingProdrugsProstateProteasome InhibitorProteinsRelapseReportingResistanceRiskSafetySamplingSerine ProteaseSmall Business Technology Transfer ResearchSolid NeoplasmSubstrate SpecificityT-LymphocyteTestingTherapeutic IndexTissuesToxic effectTransgenic MiceTumor ImmunityTumor TissueVelcadeVitamin B ComplexWorkXenograft ModelXenograft procedureadaptive immunitybasecancer cellcancer therapychemotherapeutic agentchemotherapyclinical riskcommercializationconnective tissue stromacytotoxicdesigndiphtheria toxin receptordrug candidatefibroblast-activating factorimprovedin vivokillingsmelanomaneoplastic celloverexpressionpreclinical efficacypreclinical safetyprogramsprolyl oligopeptidasepublic health relevancerecombinasetumortumor growthtumor 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):癌症是美国仅次于心脏病的第二大死亡原因。化疗是手术切除肿瘤后的主要治疗方法;但临床获益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已经开启了靶向治疗的时代。靶向驱动肿瘤生长的突变蛋白质的药物有望彻底改变癌症治疗;但癌症固有的遗传可塑性限制了肿瘤细胞的数量。
对治疗有反应的病人和那些对治疗有反应的病人往往由于产生耐药性而复发。该提案描述了旨在杀死肿瘤并减少对健康组织的损害的前药。前药被设计为保持无害,直到它们被酶成纤维细胞活化蛋白(FAP)切割。短肽连接到细胞毒性分子(肿瘤杀伤弹头)以产生前药,仅当特定的肽键被FAP酶促切割时才释放弹头。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,前药使肿瘤能够被细胞毒性剂靶向,而与癌细胞的突变状态无关。前药的可行性已在STTR I期试验中得到证实,ARI-3996可将Velcade样蛋白酶体抑制剂递送至肿瘤,ARI-3099 DOX可递送化疗剂阿霉素(DOX)。ARI-3099 DOX和ARI-3996都是有前途的候选药物。然而,在进行IND使能研究之前,将需要进一步的工作,计划用于STTR II期,以便:(1)改善前药体内半衰期,(2)
评估杀死最近被感染的FAP+细胞可能导致的安全风险。
在正常组织中发现,以及(3)了解前药是否可以通过新的作用机制缓解肿瘤免疫抑制,从而激活免疫系统杀死肿瘤[1]。Arisaph已经开发出制造前药所需的化学物质,这些前药的独特之处在于它们被FAP切割以释放细胞毒性弹头,而不是被密切相关的酶脯氨酰内肽酶切割,否则会对患者造成重大毒性风险,因为它在许多健康组织中表达。通过制备备用化合物的能力减轻了发育风险,通过使用肿瘤样品中FAP活性的简单活检测定选择患者减轻了临床风险。亚里萨的合作者H博士Borghaei(Fox Chase癌症中心)开发了一种内源性肺癌模型,用于测试前药可能的免疫学作用。STTR II期的目标是根据临床前疗效和安全性选择最有效的前药候选物,用于Arisaph在III期进行的IND使能研究。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(2)
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WILLIAM W BACHOVCHIN其他文献
WILLIAM W BACHOVCHIN的其他文献
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{{ truncateString('WILLIAM W BACHOVCHIN', 18)}}的其他基金
A Small Molecule to Activate Tumor Immunity after PLX403 in V600E BRAF Melanoma
V600E BRAF 黑色素瘤中 PLX403 后激活肿瘤免疫的小分子
- 批准号:
8835639 - 财政年份:2013
- 资助金额:
$ 53.48万 - 项目类别:
A Small Molecule to Activate Tumor Immunity after PLX403 in V600E BRAF Melanoma
V600E BRAF 黑色素瘤中 PLX403 后激活肿瘤免疫的小分子
- 批准号:
8521751 - 财政年份:2013
- 资助金额:
$ 53.48万 - 项目类别:
Using FAP to Selectively Target Epithelial Cancers
使用 FAP 选择性靶向上皮癌
- 批准号:
8295246 - 财政年份:2012
- 资助金额:
$ 53.48万 - 项目类别:
Using FAP to Selectively Target Epithelial Cancers
使用 FAP 选择性靶向上皮癌
- 批准号:
8676477 - 财政年份:2012
- 资助金额:
$ 53.48万 - 项目类别:
A Small Molecule to Activate Cetuximab to Kill K-RAS Mutant Colorectal Tumors
激活西妥昔单抗杀死 K-RAS 突变结直肠肿瘤的小分子
- 批准号:
8454845 - 财政年份:2012
- 资助金额:
$ 53.48万 - 项目类别:
Using FAP to Selectively Target Epithelial Cancers
使用 FAP 选择性靶向上皮癌
- 批准号:
8528521 - 财政年份:2012
- 资助金额:
$ 53.48万 - 项目类别:
Using FAP to Selectively Target Epithelial Cancers
使用 FAP 选择性靶向上皮癌
- 批准号:
9070390 - 财政年份:2012
- 资助金额:
$ 53.48万 - 项目类别:
A Small Molecule to Activate Cetuximab to Kill K-RAS Mutant Colorectal Tumors
激活西妥昔单抗杀死 K-RAS 突变结直肠肿瘤的小分子
- 批准号:
8647920 - 财政年份:2012
- 资助金额:
$ 53.48万 - 项目类别:
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 - 财政年份:2011
- 资助金额:
$ 53.48万 - 项目类别:
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:
8930076 - 财政年份:2011
- 资助金额:
$ 53.48万 - 项目类别:
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