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

• 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
• 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

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R 01提案是基于最近 由丹尼尔·索雷克博士与基础科学和临床研究人员密切合作领导的工作。 基于广泛的初步和试点数据，中心假设是，一种新的靶向 放射免疫治疗构建体[225 Ac] hu 11B 6将成为治疗晚期播散性和 局部晚期前列腺癌单克隆抗体hu 11B 6能够高度特异性靶向 active-hK 2是一种仅在前列腺衍生组织和前列腺癌中表达的蛋白酶， 由雄激素受体（AR）调节。虽然如果疾病被早期发现，治疗是有效的， 前列腺癌是不可治愈的，在美国每年夺去惊人的30，000人的生命。解决我们 假设使用[225 Ac] hu 11B 6的靶向α粒子放射免疫疗法可以有效地消融晚期- 阶段和传播疾病，我们提出了三个具体目标。在具体目标1（SA 1）中，我们建立了 1）骨转移模型和2） 新的侵袭性腺癌的基因工程模型，具有适当的非特异性和过量- 阻止控件。接下来，在SA 2中，我们描绘了 [225 Ac] hu 11B 6在晚期肿瘤中的应用这种严格的方法使我们能够定义生物因素 影响摄取，并在α粒子治疗 发挥其影响。SA 3建立在我们对已批准的α发射223 Ra的广泛评估的基础上， 晚期疾病使用它与[225 Ac] hu 11B 6组合。这形成了一个创新的组合阿尔法- 粒子治疗策略，通过照射癌细胞及其周围组织来增强每种药剂的功效。 周围骨转移微环境，同时避免重叠毒性。的创新之处 该提案源自[225 Ac] hu 11B 6结构的原始设计，以及对[225 Ac] hu 11B 6结构的评估。 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任务，AR- 扩增是晚期疾病发展到去势抵抗期的机制。的 所提出的方法区别于当代靶向前列腺癌放射性核素疗法（例如 作为PSMA-或铃蟾肽-靶向治疗），因为它系统地靶向肿瘤相关蛋白， 表达仅与前列腺组织相关并与AR活性相关。这些考虑 直接影响这一建议的整体影响，因为我们恭敬地提出，我们已经制定了一个 这是一种独特的有效和具体的工具，可以根除目前没有的播散性疾病病灶。 治疗正如我们的初步数据所示，这一提议有可能推动重大转变 在前列腺癌的临床治疗中。