Targeted delivery of Lu-177 to tumor vasculature
将 Lu-177 靶向递送至肿瘤脉管系统
基本信息
- 批准号:8332296
- 负责人:
- 金额:$ 98.56万
- 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:2011-09-13 至 2014-08-31
- 项目状态:已结题
- 来源:
- 关键词:AdjuvantAdjuvant TherapyAngiogenesis InhibitorsAnimalsApoptosisBindingBlood CirculationBlood VesselsBody SurfaceBreast Cancer ModelBusinessesCellsChelating AgentsClinicalCollaborationsCombined Modality TherapyDataDependenceDevelopmentDoseDoxorubicinDrug DesignDrug resistanceEndocytosisEndothelial CellsEngineeringEnvironmentFDA approvedGoalsGrowthHumanImageImmunocompetentInjection of therapeutic agentLeadLegitimacyMalignant NeoplasmsMammary NeoplasmsMediatingModelingMono-SMusNamesOutcomePatientsPenetrationPersonsPharmaceutical PreparationsPhasePhase I Clinical TrialsPositron-Emission TomographyProgression-Free SurvivalsProteinsRadiation therapyRadioisotopesRadiolabeledRadiopharmaceuticalsReceptor SignalingRecurrenceResistanceRestRoleSafetySignal TransductionSiteTherapeuticTimeTreatment EfficacyUniversitiesVascular Endothelial Growth Factor ReceptorVascular Endothelial Growth Factor Receptor-2Vascular Endothelial Growth Factorsbasebevacizumabcancer radiation therapycancer therapychemotherapycytotoxicdosimetryevidence baseexperiencein vivoinhibitor/antagonistmalignant breast neoplasmmouse modelnoveloverexpressionphase 1 studypre-clinicalradiotracerreceptorsingle photon emission computed tomographytargeted deliverytriple-negative invasive breast carcinomatumorvessel regression
项目摘要
DESCRIPTION (provided by applicant): Currently available anti-angiogenic drugs inhibit VEGF/VEGFR signaling, which leads to transient vascular regression followed by rebound of drug-resistant vasculature, which significantly decrease the therapeutic efficacy of very expensive anti-angiogenic treatment. To overcome this problem, we are developing a cytotoxic 177Lu radiopharmaceutical, scVEGF/Lu. This radiopharmaceutical is based on engineered single-chain VEGF (scVEGF) and it accumulates in tumor endothelial cells via endocytosis mediated by overexpressed VEGFR-2. In Phase I we optimized the composition of scVEGF/Lu, assessed its radiotoxicity and dosimetry and performed initial therapeutic efficacy and mechanistic studies in orthotopic breast tumor models. Our results demonstrate that a single injection of a safe dose of scVEGF/Lu induces destruction of tumor vasculature sustainable for at least 30-35 days and a widespread apoptosis in tumor without significant overall radiotoxicity. In contrast, FDA-approved sunitinib and bevacizumab failed to induce sustainable destruction of tumor vasculature, suggesting potential advantages of scVEGF/Lu. In Phase II we will focus on late pre-clinical development of scVEGF/Lu as a novel component of anti- angiogenic therapy, using orthotopic mouse models of recurrent breast cancer, including a model of human triple negative breast cancer. First, we will establish the dose- and time-dependences for scVEGF/Lu-induced destruction of tumor vasculature and potential roles of overexpressed endogenous VEGF and immunocompetent environment in therapeutic efficacy of scVEGF/Lu. Next, we will establish optimal sequence for scVEGF/Lu-doxorubicin combination as adjuvant therapy for recurrent breast cancer. Considering that scVEGF is a physiologically active protein, we will also establish the safety profile for scVEGF-PEG-DOTA conjugate. We expect that by the end of Phase II of the project we will have evidence-based indications for safe use of scVEGF/Lu in adjuvant anti-angiogenic therapy for breast cancer. We will also have a GLP-grade for dosimetry studies. This data will be used for filing IND or eIND with FDA for Phase I clinical trials with scVEGF/Lu in breast cancer. We believe that this novel targeted radiopharmaceutical may provide a new line of attack on breast cancer, and eventually will be explored for treatment of other cancers.
描述(由申请人提供):目前可用的抗血管生成药物抑制VEGF/VEGFR信号,导致短暂性血管消退,随后耐药血管反弹,这显著降低了非常昂贵的抗血管生成治疗的疗效。为了克服这个问题,我们正在开发一种具有细胞毒性的放射性药物,scVEGF/Lu。这种放射性药物基于工程单链VEGF (scVEGF),它通过过表达的VEGFR-2介导的内吞作用在肿瘤内皮细胞中积累。在I期研究中,我们优化了scVEGF/Lu的组成,评估了其放射毒性和剂量学,并在原位乳腺肿瘤模型中进行了初步的治疗效果和机制研究。我们的研究结果表明,单次注射安全剂量的scVEGF/Lu诱导肿瘤血管破坏持续至少30-35天,肿瘤细胞广泛凋亡,无明显的总体放射毒性。相比之下,fda批准的舒尼替尼和贝伐单抗未能诱导肿瘤血管的持续破坏,提示scVEGF/Lu的潜在优势。在II期,我们将专注于scVEGF/Lu作为抗血管生成治疗的新成分的后期临床前开发,使用复发性乳腺癌的原位小鼠模型,包括人类三阴性乳腺癌模型。首先,我们将建立scVEGF/Lu诱导的肿瘤血管破坏的剂量和时间依赖性,以及过表达的内源性VEGF和免疫活性环境在scVEGF/Lu治疗效果中的潜在作用。接下来,我们将建立scVEGF/ lu -阿霉素联合辅助治疗复发性乳腺癌的最佳序列。考虑到scVEGF是一种具有生理活性的蛋白,我们还将建立scVEGF- peg - dota偶联物的安全性。我们预计,在项目II期结束时,我们将获得基于证据的适应症,证明scVEGF/Lu在乳腺癌辅助抗血管生成治疗中的安全使用。我们也将有glp等级用于剂量学研究。该数据将用于向FDA提交scVEGF/Lu在乳腺癌中的I期临床试验的IND或eIND。我们相信,这种新型靶向放射性药物可能为乳腺癌提供一条新的治疗途径,并最终将探索用于治疗其他癌症。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Joseph M Backer其他文献
Joseph M Backer的其他文献
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{{ truncateString('Joseph M Backer', 18)}}的其他基金
Clinical development of 18F PET tracer for imaging VEGF receptors
用于 VEGF 受体成像的 18F PET 示踪剂的临床开发
- 批准号:
8648418 - 财政年份:2014
- 资助金额:
$ 98.56万 - 项目类别:
Clinical development of 18F PET tracer for imaging VEGF receptors
用于 VEGF 受体成像的 18F PET 示踪剂的临床开发
- 批准号:
9017150 - 财政年份:2014
- 资助金额:
$ 98.56万 - 项目类别:
Targeted photoacoustic imaging of VEGF receptors in angiogenic vasculature
血管生成血管系统中 VEGF 受体的靶向光声成像
- 批准号:
8126616 - 财政年份:2011
- 资助金额:
$ 98.56万 - 项目类别:
Targeted delivery of Lu-177 to tumor vasculature
将 Lu-177 靶向递送至肿瘤脉管系统
- 批准号:
8204231 - 财政年份:2011
- 资助金额:
$ 98.56万 - 项目类别:
Targeted delivery of Lu-177 to tumor vasculature
将 Lu-177 靶向递送至肿瘤脉管系统
- 批准号:
7745604 - 财政年份:2009
- 资助金额:
$ 98.56万 - 项目类别:
Targeting anti-apoptotic drugs to failing cardiomyocytes
将抗凋亡药物靶向衰竭的心肌细胞
- 批准号:
7271618 - 财政年份:2007
- 资助金额:
$ 98.56万 - 项目类别:
VEGF-driven PET imaging of tumor angiogenesis
VEGF 驱动的肿瘤血管生成 PET 成像
- 批准号:
7327851 - 财政年份:2007
- 资助金额:
$ 98.56万 - 项目类别:
VEGF-based Targeted Imaging of Tumor Vasculature
基于 VEGF 的肿瘤脉管系统靶向成像
- 批准号:
7271615 - 财政年份:2005
- 资助金额:
$ 98.56万 - 项目类别:
VEGF-based targeted imaging of tumor vasculature
基于 VEGF 的肿瘤脉管系统靶向成像
- 批准号:
6882122 - 财政年份:2005
- 资助金额:
$ 98.56万 - 项目类别:
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