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重新提交的 R01 提案是基于最近该工作由 Daniel Thorek 博士牵头，与基础科学和临床研究人员密切合作。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治疗结构 [225Ac]hu11B6 将成为治疗晚期播散性和单克隆抗体 hu11B6 能够高度特异性地靶向局部晚期前列腺癌。 active-hK2 是一种仅在前列腺衍生组织和前列腺癌中表达的蛋白酶，与受雄激素受体 (AR) 调节，如果疾病及早发现、传播，则治疗有效。前列腺癌是无法治愈的，在美国每年夺走 30,000 人的生命。假设使用 [225Ac]hu11B6 进行靶向 α 粒子放射免疫治疗可以有效消融晚期阶段和传播疾病，我们提出了三个具体目标，在具体目标 1 (SA1) 中，我们建立了 1) 骨转移模型和 2) 模型中构建体的整体药代动力学特征和生存获益具有适当的非特异性和过量的侵袭性腺癌的新型基因工程模型接下来，在 SA2 中，我们描述了的微观分布和放射生物学作用。 [225Ac]hu11B6 在晚期肿瘤环境中这种严格的方法使我们能够定义生物因素。影响吸收，并评估α粒子疗法的治疗反应 SA3 建立在我们对 α 发射 223Ra 模型进行广泛评估的基础上。晚期疾病将其与 [225Ac]hu11B6 组合使用，这形成了创新的组合 α-。粒子治疗策略通过照射癌细胞及其癌细胞来增强每种药物的功效围绕骨转移微环境，同时避免重叠的毒性。提案源自 [225Ac]hu11B6 构造的原始设计以及其评估反映致命晚期疾病生物学的先进模型有一个明确的生物学指令：AR- 放大是晚期疾病发展到去势抵抗阶段的机制。所提出的方法与当代靶向前列腺癌放射性核素疗法（例如作为 PSMA 或铃蟾肽靶向疗法），因为它系统地靶向肿瘤相关蛋白，该蛋白表达仅与前列腺组织相关，并与 AR 活性相关。直接影响该提案的总体影响，因为我们恭敬地提出，我们已经制定了独特有效且具体的工具，可根除目前尚无治疗方法的播散性疾病灶正如我们的初步数据所示，该提案有可能引发重大转变。在前列腺癌的临床治疗中。