Combined Biologic and Radiopharmaceutical Therapy of Breast Cancer

乳腺癌的生物和放射药物联合治疗

• 批准号: 8914075
• 负责人: George Sgouros
• 金额: $ 47.77万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/8914075
• 关键词: Address; Adverse effects; Alpha Particles; Animal Model; Antibodies; Binding; Biological Response Modifiers; Breast Cancer Model; Breast Cancer therapy; Breast cancer metastasis; Cancer Control; Cell Culture Techniques; Cells; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Combined Modality Therapy; Cytotoxic Chemotherapy; DNA; DNA Damage; DNA Repair; DNA strand break; Data; Disease; Disseminated Malignant Neoplasm; Dose-Limiting; Drug Kinetics; Exhibits; FDA approved; Genetic Transcription; Grant; Heterogeneity; Human; Human Experimentation; Imatinib; Implant; In Vitro; Indigenous; Inflammation; Investments; Lead; Lung; Malignant Neoplasms; Maximum Tolerated Dose; Mediating; Metabolic Pathway; Modality; Modeling; Molecular; Mutation; Neoplasm Metastasis; Normal Cell; Observational Study; Operative Surgical Procedures; Organ; Organ Survival; Pathway interactions; Patients; Pharmacologic Substance; Photons; Physiological; Pre-Clinical Model; Proliferating; Proteins; Radiation; Radiation therapy; Radiopharmaceuticals; Rattus; Recommendation; Reporting; Research Design; Resistance; Signal Pathway; Testing; Therapeutic; Time; Toxic effect; Transgenic Model; Transgenic Organisms; Translating; Trastuzumab; Treatment Efficacy; Tumor Necrosis Factor-alpha; Vorinostat; antibody conjugate; base; cancer cell; cancer therapy; cell killing; chemotherapy; clinically relevant; cytotoxic; dosimetry; falls; in vivo; inhibitor/antagonist; malignant breast neoplasm; monolayer; mouse model; neoplastic cell; novel; particle; pre-clinical; preclinical study; public health relevance; repaired; research study; resistance mechanism; response; success; trial design; tumor

 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（通过应用提供）：放射性药物治疗（RPT）是化学疗法的高度有希望的替代方法。它也是一种与生物学或途径抑制作用的疗法。 RPT利用与肿瘤结合的药物，以专门为靶细胞提供辐射。最有希望的RPT使用α粒子发射器（αRPT）。 α粒子在很大程度上导致无法弥补的DNA损伤；靶向独立于信号通路。大多数αRPT研究都集中在腔内施用，这些卫段施用将αRPT限制在与肿瘤细胞相同的空间上，对这种类型的研究并未提供在更广泛的传播转移设置中实现αRPT所需的临床前数据。在乳腺癌转移的转基因前临床前模型中，我们先前已经证明了α-Emitters 213Bi（T1/2 = 46分钟）和225AC（T1/2 = 10 d;4α的每衰减）的效率，结合到抗体中。基于这些研究以及在某些情况下治疗不会导致长期治疗的观察，我们建议用生物反应修饰剂（BRMS）研究αRPT。以前尚未报道组合αRPT-BRM研究。重点是将αRPT与细胞毒性化学疗法结合在一起。 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. α-颗粒发射器的AB偶联物213b，211AT或225AC与参与调节的BRMS结合：注射（TNF-α），蛋白质成熟（17-AAG），基因转录（SAHA）和DNA修复（NU7441），将在VITO中使用单层细胞培养物进行研究。 2。评估AIM 1中确定的αRPT/BRM组合的药代动力学，有效性和毒性以进行进一步研究。评估微型（子管制）和宏观（全器）水平的肿瘤和正常器官分布和药代动力学。确定每种组合的剂量限制器官（DLO）和最大耐受剂量（MTD）。 3。开发一种药物/剂量测定模型，以符合目标1和2中获得的响应/毒性数据。使用该模型确定最大程度影响效率和毒性的参数集。将临床前观察转换为人类试验设计的建议。带有α-发射体的RPT是一种与化学疗法和途径抑制疗法不同的治疗方法。它非常适合治疗 转移性疾病，当前治疗方案失败的疾病。在转移性疾病的临床前模型中理解和优化αRPT的努力将在降低人类实验范围方面提供大量投资回报，尤其是在联合治疗的背景下。对该提案的支持将使αRPT对转移酶进行更有效，毒性更少的实施。