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

项目描述- 约翰霍普金斯大学医学院重新提交的这份R01提案是基于最近 丹尼尔·索雷克博士与基础科学和临床研究人员密切合作开展的工作。 基于广泛的初步和试点数据，中心假设是一个新的有针对性的 放射免疫治疗构建体[225Ac]hu11B6将成为治疗晚期播散性和非霍奇金淋巴瘤的重要工具 局部晚期前列腺癌。单抗hu11B6可实现高度特异性的靶向 Active-HK2，一种仅在前列腺癌和前列腺癌组织中表达的蛋白，与前列腺癌 受雄激素受体(AR)调节。虽然治疗是有效的，如果疾病被及早发现，传播 前列腺癌是不治之症，在美国每年夺走3万人的生命。向我们的 [225Ac]hu11B6靶向α粒子放射免疫治疗可有效消融晚期高血压的假说 对于分期和播散性疾病，我们提出了三个具体目标。在具体目标1(SA1)中，我们建立 在1)骨转移和2)骨转移模型中构建的全球药代动力学分布和生存益处 侵袭性腺癌的新基因工程模型具有适当的非特异性和过度- 被阻止的控件。接下来，在SA2中，我们描述了微生物的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 影响摄取，并在阿尔法粒子治疗的范围内评估治疗反应 发挥它的作用。SA3建立在我们对批准的阿尔法发射223Ra的广泛评估基础上 晚期疾病可与[225Ac]hu11B6联合使用。这形成了一种创新的组合阿尔法- 粒子治疗策略，通过照射癌细胞和癌细胞来提高每种药物的疗效 周围骨转移微环境，同时避免重叠毒性。它的创新之处在于 该提案来自[225Ac]hu11B6结构的原始设计，此外还在 反映致命的晚期疾病生物学的高级模型。有一个明确的生物学授权，AR- 扩增是晚期疾病发展到去势抵抗阶段的机制。这个 所提出的方法有别于当代靶向前列腺癌放射性核素疗法(如 作为PSMA或蛙皮素靶向疗法)，因为它系统地靶向肿瘤相关蛋白，其 其表达仅与前列腺组织相关，并与AR活性相关。这些考虑因素 直接影响这项提案的整体影响，因为我们恭敬地提出，我们已经制定了一项 独一无二的强大而具体的工具，可根除目前尚无治疗方法的播散性疾病 治疗。正如我们的初步数据所表明的那样，这一提议有可能推动重大转变 在前列腺癌的临床治疗中。

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.