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: 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
• 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

 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）：放射性药物治疗（RPT）是一种非常有前途的化疗替代方案。它也是一种与生物或途径抑制疗法正交的治疗。RPT利用与肿瘤结合的药物将辐射特异性地传递到靶细胞。最有前途的RPT使用α粒子发射体（αRPT）。α粒子造成的DNA损伤在很大程度上是不可修复的;靶向是独立的信号通路。大多数αRPT研究都集中在将αRPT限制在与肿瘤细胞相同空间的腔内给药上，此类研究无法提供在更广泛的扩散转移环境中实施αRPT所需的临床前数据。在乳腺癌转移的转基因临床前模型中，我们先前已经证明了α-发射体213 Bi（T1/2=46 min）和225 Ac（T1/2=10 d;每次衰变4个α）与抗体结合的有效性。基于这些研究以及在某些情况下治疗不能导致长期治愈的观察结果，我们建议使用生物反应调节剂（BRM）研究αRPT。既往未报告αRPT-BRM联合研究;重点是αRPT与细胞毒性化疗联合。假设αRPT最好与BRM而不是直接具有细胞毒性的药物联合使用，并且最好通过临床前研究获得用于临床实施的组合，并通过建模和剂量测定分析支持将结果外推至人体临床试验设计，我们提出以下目标：1.在体外鉴定导致最大肿瘤细胞杀伤的αRPT/BRM组合。将使用单层和球状体细胞培养条件，在体外研究α粒子发射体213 B、211 At或225 Ac与参与调节炎症（TNF-α）、蛋白质成熟（17-AAG）、基因转录（SAHA）和DNA修复（NU 7441）的BRM组合的Ab缀合物。2.评估目标1中确定的αRPT/BRM复方制剂的药代动力学、疗效和毒性，以进行进一步研究。在微观（亚器官）和宏观（全器官）水平上评价肿瘤和正常器官分布和药代动力学。确定剂量限制性器官（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，以拟合目标1和2中获得的反应/毒性数据。使用该模型确定对疗效和毒性影响最大的参数集。将临床前观察结果转化为人体试验设计的建议。使用α-发射体的RPT是一种与化疗和通路抑制疗法不同的治疗方法。它非常适合治疗 转移性疾病，一种目前治疗方案失败的疾病。在转移性疾病的临床前模型中了解和优化αRPT的努力将在减少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。支持这一提议将使αRPT对转移酶的应用更有效、毒性更低。