Interactions Between Cytotoxic and Antiangiogenic Drugs

细胞毒性药物和抗血管生成药物之间的相互作用

• 批准号: 8204789
• 负责人: James M. Gallo
• 金额: $ 22.9万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204789
• 关键词: Address; Affect; Alkylating Agents; Angiogenesis Inhibitors; Angiogenic Factor; Behavior; Blood Vessels; Brain Neoplasms; Cell surface; Characteristics; Clinic; Clinical Research; Clinical Trials; Complex; Cytotoxic agent; Data; Databases; Development; Drug Combinations; Drug Delivery Systems; Drug Interactions; Drug Kinetics; Drug resistance; Effectiveness; Ensure; Epidermal Growth Factor Receptor; Foundations; Gene Expression; Gene Proteins; Glioma; Goals; Growth; Hybrids; Investigation; Lead; Measurement; Measures; Mediating; Modeling; Molecular; Monitor; Mus; Nature; Neoplasms in Vascular Tissue; Outcome; PDGFRB gene; PTEN gene; Patients; Pharmaceutical Preparations; Pharmacodynamics; Process; Property; Regimen; Research; Resistance; Resistance profile; Series; Solid Neoplasm; Translating; Treatment outcome; Tumor Angiogenesis; Vascular Endothelial Growth Factor Receptor; angiogenesis; base; cytotoxic; design; improved; in vivo; inhibitor/antagonist; novel; pharmacodynamic model; pre-clinical; prospectuses; protein expression; public health relevance; resistance mechanism; response; subcutaneous; temozolomide; tumor

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.

描述（由申请人提供）：实体瘤的生长和侵袭性高度依赖于血管生成或形成新肿瘤血管的过程。因此，抗血管生成药物的开发相当重要，但最近的临床试验表明，早期良好的患者反应并不持久，这归因于耐药性。耐药机制的复杂性和多样性要求采用系统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，以克服对血管生成抑制剂的耐药性，并进一步确保共同给药的细胞毒性药物能够以足够的量到达肿瘤。为了实现这一目标，提出了三个目标，描述基于肿瘤药物特性的一系列药代动力学 (PK) 和药效学 (PD) 研究。目标 1 研究将在体内衍生抗血管生成药物耐药性脑肿瘤，并比较细胞毒性药物替莫唑胺 (TMZ) 在敏感和耐药肿瘤中的肿瘤积累。将监测与血管生成相关的基因和蛋白质的表达以创建耐药性概况。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标来干扰血管生成的多靶点药物组合。所选择的药物组合将部分基于目标 1 中确定的耐药情况。在确定抑制耐药性的多靶点药物组合后，将进行最后一组研究来分析 TMZ 肿瘤递送和称为血管正常化的过程，有效药物输送的标志。与目标 1 一样，目标 2 中将获得 PK（即药物浓度）和 PD（基因和蛋白质表达）测量值，以提供强大的数据库来制定有效组合的 PK/PD 模型，这也是目标 3 的目标。具体来说，我们将建立基于生理学的 PK/PD 模型，提供一种外推到患者的方法，以便可以预测脑肿瘤中的 PK 和 PD 终点。该项目背后的定量药理学方法使信息能够更加无缝地流入临床，有望为设计复杂的多药治疗方案提供合理的范例。 公共健康相关性：最近的临床研究表明，由于耐药性的发展，抗血管生成药物对实体瘤的有效性是暂时的。通过使用对血管生成抑制剂具有耐药性的临床前脑肿瘤模型，我们将开发克服耐药性的靶向药物组合，并进一步使共同给药的细胞毒性药物能够成功递送至肿瘤。定量药理学模型将被推导并外推到患者身上，以便对患者实施合理有效的多药治疗。