Combined Biologic and Radiopharmaceutical Therapy of Breast Cancer

 描述(由申请人提供)：放射性药物治疗(RPT)是一种非常有希望的化疗替代方法。它也是一种与生物疗法或途径抑制疗法正交的疗法。RPT利用与肿瘤结合的药物将辐射专门传递到目标细胞。最有前景的RPT使用α-粒子发射器(αRPT)。阿尔法粒子造成的DNA损伤在很大程度上是不可修复的；靶向与信号通路无关。大多数α放射治疗研究集中在腔内给药，将α放射治疗限制在与肿瘤细胞相同的空间内，这类研究没有提供在更广泛的播散转移环境中实施α放射治疗所需的临床前数据。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213Bi(t1/2=46min)和225Ac(t1/2=10d；每个衰变4α‘S)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并不能导致长期治愈的观察，我们建议使用生物反应调节剂(BRM)来研究αRPT。联合αRPT-BRM的研究以前未见报道；焦点一直集中在αRPT与细胞毒化疗的联合应用上。假设αRPT，最好与BRM结合，而不是直接具有细胞毒性的药物，并且临床应用的组合是通过临床前研究获得的最佳组合，并通过建模和剂量分析支持将结果外推到人类临床试验设计，我们提出以下目标：1.确定在体外导致最大肿瘤细胞杀伤的αRPT/BRM组合。α粒子发射体213B、211At或225Ac与参与调节的BRM的AB结合物将在体外使用单层和球状细胞培养条件进行研究，这些BRM参与调节：炎症(肿瘤坏死因子-α)、蛋白质成熟(17-AAG)、基因转录(SAHA)和DNA修复(NU7441)。2.评估目标1中确定的αRPT/BRM组合的药代动力学、疗效和毒性，以供进一步研究。在微观(亚器官)和大尺度(整体器官)水平评估肿瘤和正常器官的分布和药代动力学。确定每种组合的剂量限制器官(DLO)和最大耐受剂量(MTD)。3.建立药代动力学/剂量学模型来拟合AIMS 1和2中获得的反应/毒性数据。使用该模型来确定对疗效和毒性影响最大的一组参数。将临床前的观察转化为人体试验设计的建议。带α发射体的RPT是一种不同于化疗和途径抑制治疗的治疗方法。它非常适合于治疗 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。对这一提议的支持将使更有效和毒性更低的αRPT针对转移瘤实施。

 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.