Interactions Between Cytotoxic and Antiangiogenic Drugs

描述(申请人提供)：实体肿瘤的生长和侵袭力高度依赖于血管生成或形成新的肿瘤血管的过程。因此，抗血管生成药物的开发具有相当重要的意义，然而最近的临床试验表明，患者早期良好的反应并不持久，这被归因于耐药性。耐药机制的复杂性和多样性要求采用系统的方法来定义新的治疗范例，以减轻对血管生成抑制剂的耐药性。该项目的总体目标是为设计多药联合方案提供临床前基础，这些方案将克服对血管生成抑制剂的耐药性，并进一步确保联合应用的细胞毒药物将达到足够数量的肿瘤。为了实现这一目标，根据肿瘤药物的性质，提出了描述一系列药代动力学(PK)和药效学(PD)研究的三个目标。目的1比较细胞毒药物替莫唑胺(TMZ)在敏感和耐药肿瘤中的蓄积情况。将监测与血管生成相关的基因和蛋白的表达，以创建耐药概况。最初的目标2研究再次利用耐药肿瘤，将评估通过抑制细胞表面和细胞内靶点而干扰血管生成的多靶点药物组合。选择的药物组合将部分基于目标1中确定的耐药情况。在确定抑制耐药的多靶点药物组合后，将进行最后一组研究，以分析TMZ肿瘤递送和被称为血管正常化的过程，这是有效药物递送的标志。与目标1一样，目标2将获得PK(即药物浓度)和PD(基因和蛋白质表达)测量，以提供一个强大的数据库来制定有效组合的PK/PD模型，这是目标3的目标。具体地说，我们将建立基于生理学的PK/PD模型，为患者提供一种外推方法，以便可以预测脑瘤的PK和PD终点。该项目背后的定量药理学方法使信息能够更无缝地流入临床，有望为设计复杂的多药方案提供一个合理的范例。 公共卫生相关性：最近的临床研究表明，由于耐药性的产生，抗血管生成药物对实体肿瘤的疗效是暂时的。通过使用对血管生成抑制剂具有耐药性的临床前脑瘤模型，我们将开发克服耐药性的靶向药物组合，并进一步使联合给药的细胞毒药物能够成功地输送到肿瘤。定量药理学模型将被推导出来，并外推到患者身上，以便在患者身上实施合理有效的多药治疗。

DESCRIPTION (provided by applicant): The growth and invasiveness of solid tumors is highly dependent on angiogenesis or the processes forming new tumor blood vessels. Accordingly the development of antiangiogenic drugs is of considerable importance, yet recent clinical trials have demonstrated that early favorable patient responses are not durable, which has been attributed to drug resistance. The complex and diverse nature of the drug resistance mechanisms calls for a systematic approach to define new treatment paradigms to alleviate resistance to angiogenesis inhibitors. The overall objective of the project is to provide a preclinical foundation to design multidrug combination regimens that will overcome resistance to angiogenesis inhibitors and further ensure that coadministered cytotoxic drugs will reach tumors in sufficient amounts. To accomplish this objective, three Aims are proposed that describe a series of pharmacokinetic (PK) and pharmacodynamic (PD) investigations based on the properties of the drugs in tumors. Aim 1 studies will derive antiangiogenic drug resistant brain tumors in vivo and compare the tumor accumulation of the cytotoxic drug, temozolomide (TMZ) in sensitive and resistant tumors. The expression of genes and proteins relevant to angiogenesis will be monitored to create a resistance profile. Initial Aim 2 studies, again utilizing drug resistant tumors, will evaluate multitargeted drug combinations that interfere with angiogenesis by inhibiting targets on the cell surface and intracellularly. The drug combinations selected will be, in part, based on the resistance profiles determined in Aim 1. Upon identifying multitargeted drug combinations that suppress resistance, a final set of studies will be undertaken to analyze TMZ tumoral delivery and the process referred to as vascular normalization, a hallmark of effective drug delivery. As in Aim 1, PK (i.e. drug concentrations) and PD (gene and protein expression) measurements will be obtained in Aim 2 to provide a robust database to formulate PK/PD models for the effective combinations, which is the goal of Aim 3. Specifically, we will build physiologically-based PK/PD models that offer a means to be extrapolated to patients so that PK and PD endpoints can be predicted in brain tumors. The quantitative pharmacological approach underlying the project enables a more seamless pipeline of information to flow into the clinic that hopefully will provide a rational paradigm to design complex multidrug regimens. PUBLIC HEALTH RELEVANCE: Recent clinical studies indicate that the effectiveness of antiangiogenic drugs against solid tumors is temporary due to the development of drug resistance. By using preclinical brain tumor models resistant to angiogenesis inhibitors we will develop targeted drug combinations that overcome resistance, and further, enable coadministered cytotoxic drugs to be successfully delivered to the tumor. Quantitative pharmacological models will be derived and extrapolated to patients so that rational and effective multidrug therapy can be implemented in patients.