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（由申请人证明）：放射性药物治疗（RPT）是对化学疗法的高度有希望的RPT使用α-粒子发射器（αRPT）。 αRPT在较宽的传播转移中。 NT在某些组合αRPT-BRM研究中没有导致长期治愈，这不是将αRPT与细胞毒性化学疗法结合在一起的。而且，结合实施方法是通过临床前支持的静脉和剂量法分析获得的，该分析将外外向人类的临床试验设计外，识别导致调节中最大的肿瘤细胞杀死的M组合：炎症（TNF-α），蛋白质成熟（17）（17 - AAG），基因转录（SAHA）和DNA修复（NU7441）将在体外研究单层和球形培养培养物菌群colture coluture coluture coluture colution notics notther and os 1 AL AIM 1。（全器）水平观察到人类试验设计的建议。当前的治疗选择失败的转移性疾病将在减少人类实验范围的投资中提供投资，T组合Herapy支持堡垒将使对转移酶的αRPT有效实施。