Kallikrein-Targeted Alpha-Particle Therapy of Late-Stage Prostate Cancer

激肽释放酶靶向阿尔法粒子治疗晚期前列腺癌

基本信息

批准号：
9236277
负责人：
Daniel Lyndon Jaffe Thorek
金额：
$ 37.33万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-15 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9236277
关键词：
Actinium Address Adenocarcinoma Advanced Malignant Neoplasm Affect Alpha Cell Alpha Particle Emitter Alpha Particles Androgen Receptor Antibodies Antineoplastic Agents Basic Science Biochemistry Biological Biological Factors Biology Bombesin Caliber Cancer Etiology Cells Cessation of life Clinical Clinical Chemistry Clinical Investigator Clinical Management Clinical Trials Collaborations Data Development Diagnostic radiologic examination Discipline of Nuclear Medicine Disease Disease Resistance Distributional Activity Dose Drug Kinetics Evaluation FOLH1 gene Genetic Engineering Genetically Engineered Mouse Goals Histocytochemistry Human Human Glandular Kallikrein 2 Image Immunofluorescence Immunologic Implant Investigational Therapies Kininogenase LNCaP Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of prostate Memorial Sloan-Kettering Cancer Center Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Microscopic Modeling Molecular Monitor Neoplasm Metastasis Organ Outcome Pathology Pathway interactions Patients Peptide Hydrolases Pharmaceutical Preparations Positron-Emission Tomography Production Prostate Prostate Adenocarcinoma Prostate carcinoma Proteins Quality of life Radiation Oncology Radiation therapy Radioimmunotherapy Radiology Specialty Records Renal function Resistance Seeds Serum Site Soft Tissue Disorder Soil Survival Rate Testing Therapeutic Tissues Toxic effect Toxicology Transgenic Model Tumor Tissue Tumor Volume United States Universities Urology VCaP Work advanced disease antitumor effect base bone burden of illness cancer cell cancer radionuclide therapy clinical toxicology curative treatments cytotoxic design dosimetry effective therapy falls humanized monoclonal antibodies improved innovation insight liver function medical schools men mouse model novel overexpression particle therapy prostate cancer cell prostate cancer model soft tissue targeted agent targeted treatment tool treatment response tumor uptake

项目摘要

PROJECT DESCRIPTION – This R01 proposal resubmission from The Johns Hopkins University School of Medicine is founded on recent work spearheaded by Dr. Daniel Thorek in close collaboration with basic science and clinical investigators. Based upon extensive preliminary and pilot data, the central hypothesis is that a novel targeted radioimmunotherapy construct, [225Ac]hu11B6, will be an important tool to treat late-stage disseminated and locally advanced prostate cancer. The monocloncal antibody hu11B6 enables highly specific targeting of active-hK2, a protease solely expressed in prostate-derived tissues and prostate carcinoma, that is tightly regulated by the androgen receptor (AR). While treatment is effective if disease is detected early, disseminated prostate cancer is incurable and claims a staggering 30,000 lives/year in the United States. To address our hypothesis that targeted alpha-particle radioimmunotherapy with [225Ac]hu11B6 can effectively ablate late- stage and disseminated disease, we propose three Specific Aims. In Specific Aim 1 (SA1) we establish the global pharmacokinetic profile and survival benefit of the construct in models of 1) osseous metastases and 2) novel genetically engineered models of aggressive adenocarcinoma with appropriate non-specific and excess- blocked controls. Next, in SA2 we profile the microscopic distribution and radiobiological action of [225Ac]hu11B6 in the advanced tumor setting. This rigorous approach enables us to define biological factors which influence uptake, and to evaluate treatment response at the scale upon which alpha-particle therapy exerts its effects. SA3 builds upon our extensive evaluation of the approved alpha-emitting 223Ra in models of advanced disease to use it in combination with [225Ac]hu11B6. This forms an innovative combination alpha- particle therapy strategy to enhance the efficacy of each agent by irradiating both the cancer cells and their surrounding bone metastatic microenvironment, while avoiding overlapping toxicities. The innovation of this proposal derives from the original design of the [225Ac]hu11B6 construct in addition to its evaluation in advanced models that reflect fatal late-stage disease biology. There is a clear biological mandate that AR- amplification is the mechanism by which advanced disease develops to the castrate resistant stage. The proposed approach is distinguished from contemporary targeted prostate cancer radionuclide therapies (such as PSMA- or bombesin-targeting therapies) in that it systematically targets a tumor-associated protein whose expression is exclusively associated with prostate tissue and correlates with AR-activity. These considerations directly influence the overall impact of this proposal, as we respectfully submit that we have developed a uniquely potent and specific tool to eradicate disseminated foci of disease for which there is no current treatment. As indicated by our Preliminary Data, this proposal has the potential to motivate a significant shift in the clinical management of prostate cancer.

项目描述 - 约翰·霍普金斯大学医学院的R01提案重新提交是基于最近的由丹尼尔·托雷克（Daniel Thorek）博士与基础科学和临床研究人员密切合作的工作。基于广泛的初步和试点数据，中心假设是一种新颖的目标放射免疫疗法构建[225AC] HU11B6将是治疗晚期散布和的重要工具局部晚期前列腺癌。单克隆抗体HU11B6实现了高度特异的靶向 Active-HK2，一种仅在前列腺衍生的组织和前列腺癌中表达的蛋白酶，紧密由雄激素受体（AR）调节。虽然如果早日检测到疾病，则治疗是有效的前列腺癌是无法治愈的，在美国拥有惊人的30,000人生。解决我们的假设[225AC] HU11B6靶向α粒子放射性疗法可以有效地消融阶段和传播疾病，我们提出了三个具体目标。在特定目标1（SA1）中，我们建立了在1）骨转移和2的模型中，构建体的全局药代动力学特征和生存优势具有适当非特异性且超过 - 阻塞控件。接下来，在SA2中，我们介绍了微观分布和放射生物学作用 [225AC] HU11B6在晚期肿瘤设置中。这种严格的方法使我们能够定义生物学因素哪些影响摄取并评估α粒子治疗的尺度上的治疗反应发挥作用。 SA3建立在我们对批准的α发射223RA的广泛评估基础上晚期疾病将其与[225AC] HU11B6结合使用。这形成了创新的组合alpha- 通过照射癌细胞及其它们的粒子治疗策略，以提高每种药物的效率围绕骨转移的微环境，同时避免了重叠的战术。这个创新提案源自[225AC] HU11B6结构的原始设计，此外反映致命后期疾病生物学的高级模型。有明确的生物学任务，即放大是晚期疾病到castrate抗性阶段发展的机制。这所提出的方法与当代靶向前列腺癌辐射疗法有所区别（这样作为pSMA或孟买靶向疗法），因为它是系统地靶向肿瘤相关蛋白的表达与前列腺组织仅相关，并与AR活性相关。这些考虑直接影响该提案的整体影响，因为我们谨慎地认为我们已经开发了具有疾病的放射性传播灶的独特潜力和特定工具，没有电流治疗。正如我们的初步数据所示，该提案有可能激发重大转变在前列腺癌的临床管理中。