Combined Biologic and Radiopharmaceutical Therapy of Breast Cancer

乳腺癌的生物和放射药物联合治疗

基本信息

批准号：
9261492
负责人：
George Sgouros
金额：
$ 47.7万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9261492
关键词：
Address Adverse effects Alpha Particle Emitter Alpha Particles Animal Model Antibodies Binding Biological Response Modifiers Breast Cancer Model Breast Cancer therapy Cancer Control Cell Culture Techniques Cells Clinical Clinical Data Clinical Trials Clinical Trials Design Combined Modality Therapy Cutaneous Cytotoxic Chemotherapy DNA DNA Damage DNA Repair DNA strand break Data Disease Disseminated Malignant Neoplasm Dose-Limiting Drug Kinetics ERBB2 gene Exhibits FDA approved Genetic Transcription Grant Heterogeneity Human Human Experimentation Imatinib Implant In Vitro Indigenous Inflammation Investments Lead Malignant Neoplasms Maximum Tolerated Dose Mediating Metabolic Pathway Metastatic Neoplasm to the Lung Modality Modeling Molecular Neoplasm Metastasis Normal Cell Operative Surgical Procedures Organ Pathway interactions Patients Pharmacologic Substance Photons Physiological Pre-Clinical Model Proliferating Proteins Radiation Radiation therapy Radiopharmaceuticals Rattus Recommendation Reporting Research Design Resistance Signal Pathway TNF gene Testing Therapeutic Time Toxic effect Transgenic Model Transgenic Organisms Translating Trastuzumab Treatment Efficacy Vorinostat actionable mutation antibody conjugate base cancer cell cancer therapy cell killing chemotherapy clinically relevant cytotoxic dosimetry experimental study falls in vivo inhibitor/antagonist malignant breast neoplasm monolayer mouse model neoplastic cell novel pre-clinical preclinical study public health relevance repaired resistance mechanism response success systemic toxicity trial design tumor

项目摘要

DESCRIPTION (provided by applicant): Radiopharmaceutical therapy (RPT) is a highly promising alternative to chemotherapy. It is also a treatment that is orthogonal to biologic, or pathway inhibition, therapy. RPT exploits pharmaceuticals that bind to tumors to deliver radiation specifically to the targeted cells. The most promising RPT uses α-particle emitters (αRPT). Alpha-particles cause largely irreparable DNA damage; targeting is independent of signaling pathways. The majority of αRPT studies have focused on intracavitary administrations that confine the αRPT to the same space as the tumor cells, studies of this type do not provide the pre-clinical data required to implement αRPT in a wider disseminated metastasis setting. In a transgenic pre-clinical model of breast cancer metastases, we have previously demonstrated the efficacy of the α-emitters 213Bi (T1/2=46 min) and 225Ac (T1/2=10 d; 4 α's per decay), conjugated to an antibody. Based on these studies and the observation that treatment did not lead to long-term cure under some circumstances, we propose to investigate αRPT with biologic response modifiers (BRMs). Combination αRPT-BRM studies have not been reported previously; the focus has been on combining αRPT with cytotoxic chemotherapy. Under the hypothesis that αRPT, is best combined with BRMs rather than agents that are directly cytotoxic and that the combination for clinical implementation is best obtained by preclinical studies supported with the modeling and dosimetry analysis that will enable extrapolation of results to human clinical trial design, we propose the following aims: 1. Identify αRPT/BRM combinations that lead to the greatest tumor cell kill, in vitro. Ab-conjugates of the α-particle emitters 213B, 211At or 225Ac in combination with BRMs involved in modulating: inflammation (TNF-α), protein maturation (17-AAG), gene transcription (SAHA) and DNA repair (NU7441) will be investigated, in vitro, using monolayer and spheroid cell culture conditions. 2. Assess pharmacokinetics, efficacy and toxicity of the αRPT/BRM combinations identified in Aim 1 for further study. Evaluate tumor and normal organ distribution and pharmacokinetics at the micro (sub-organ) and macroscale (whole-organ) level. Determine the dose-limiting organ (DLO), and maximum tolerated dose (MTD) for each combination. 3. Develop a pharmarcokinetic/dosimetry model to fit response/toxicity data obtained in Aims 1 and 2. Use the model to identify the set of parameters that most impacts efficacy and toxicity. Translate pre-clinical observations into recommendations for human trial design. RPT with α-emitters is a treatment approach that is distinct from chemotherapy and pathway inhibition therapy. It is ideally suited to the treatment of metastatic disease, a condition in which current treatment options fail. Efforts to understand and optimize αRPT in pre-clinical models of metastatic disease will provide a substantial return on investment in terms of reducing the scope of human experimentation, especially in the context of combination therapy. Support for this proposal will enable a more effective and less toxic implementation of αRPT against metastatases.

描述（由申请人提供）：放射性药物疗法（RPT）是一种非常有前途的化疗替代方案，它也是一种与生物疗法或途径抑制疗法正交的治疗方法，RPT 利用与肿瘤结合的药物来特异性地向肿瘤递送放射线。最有前途的 RPT 使用 α 粒子发射器 (αRPT)，其导致的 DNA 损伤很大程度上是不可修复的；大多数 αRPT 研究表明，靶向作用与信号通路无关。此类研究侧重于将 αRPT 限制在与肿瘤细胞相同空间的腔内给药，但未提供在乳腺癌转基因临床前模型中在更广泛的播散性转移环境中实施 αRPT 所需的临床前数据。转移，我们之前已经证明了 α 发射体 213Bi (T1/2=46 分钟) 和 225Ac (T1/2=10 d；每次衰变 4 个 α），基于这些研究以及在某些情况下治疗不会导致长期治愈的观察，我们建议研究 αRPT 与生物反应调节剂（BRM）的组合。此前尚未报道过 BRM 研究；重点是 αRPT 与细胞毒性化疗相结合，假设 αRPT 最好与 BRM 联用，而不是与直接细胞毒性药物联用，并且该组合适用于临床。实施最好通过建模和剂量分析支持的临床前研究来实现，这将能够将结果外推到人类临床试验设计中，我们提出以下目标： 1. 确定在体外导致最大肿瘤细胞杀灭的 αRPT/BRM 组合α-粒子发射体 213B、211At 或 225Ac 的 Ab 结合物与参与调节的 BRM 结合：炎症 (TNF-α)、蛋白质成熟(17-AAG)、基因转录 (SAHA) 和 DNA 修复 (NU7441) 将使用单层和球状细胞培养条件进行体外研究 2. 评估目标 1 中确定的 αRPT/BRM 组合的药代动力学、功效和毒性。评估肿瘤和正常器官的分布以及微观（亚器官）和宏观（整个器官）水平的药代动力学，确定剂量限制器官。 (DLO) 和每种组合的最大耐受剂量 (MTD) 3. 开发药代动力学/剂量测定模型以适应目标 1 和 2 中获得的反应/毒性数据。使用该模型来确定最影响功效和效果的参数集。将临床前观察结果转化为人体试验设计的建议。RPT 是一种不同于化疗和通路抑制疗法的治疗方法，非常适合治疗以下疾病。转移性疾病是目前治疗方案失败的一种情况，在转移性疾病临床前模型中理解和优化 αRPT 的努力将在缩小人体实验范围方面提供可观的投资回报，特别是在联合治疗的背景下。对该提案的支持将使αRPT针对转移瘤的实施更加有效且毒性较小。