Targeting Tumor Angiogenesis with SAHA and Bevacizumab in Kidney Cancer

SAHA 和贝伐珠单抗靶向肾癌中的肿瘤血管生成

• 批准号: 7275885
• 负责人: Roberto Pili
• 金额: $ 24.91万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-24 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275885
• 关键词: Angiogenesis Inhibitors; Angiogenesis Pathway; Asses; Avastin; Biological; Biometry; Blood Platelets; Breast Carcinoma; Cancer Therapy Evaluation Program; Cell Proliferation; Class; Clear Cell; Clinical; Combined Modality Therapy; Correlative Study; Couples; Development; Differentiation Inducer; End Point; Endothelial Cells; Epigenetic Process; Epithelial; Foundations; Future; Gene Expression; Genes; Genetic; Goals; Grant; Growth Factor; Growth Factor Overexpression; Histone Deacetylase Inhibitor; Histones; Human; Hydroxamic Acids; Image; In Vitro; Lung; Malignant Neoplasms; Malignant neoplasm of kidney; Metastatic Renal Cell Cancer; Pathway interactions; Patients; Pharmacodynamics; Pharmacology; Phase; Phase II/III Trial; Production; Renal Cell Carcinoma; Renal carcinoma; Reporting; Research; Research Personnel; Role; Signal Transduction; Solid Neoplasm; Source; Testing; Therapeutic; Time; Transcriptional Regulation; Tumor Angiogenesis; Tumor Biology; Tyrosine Kinase Inhibitor; United States Food and Drug Administration; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vorinostat; Work; angiogenesis; antiangiogenesis therapy; base; bevacizumab; cancer imaging; cancer therapy; chemotherapy; drug development; humanized monoclonal antibodies; hypoxia inducible factor 1; in vivo; inhibitor/antagonist; innovation; insight; interest; medical schools; metastatic colorectal; neoplastic cell; novel; novel therapeutics; pre-clinical; tumor; uptake; urologic

DESCRIPTION (provided by applicant): Tumor angiogenesis is critical for the development and progression of epithelial tumors including renal cell carcinoma (RCC). Differentiating agents such as the inhibitors of histone deacetylases (HDACs) have been shown to exert their antitumor effect by gene modulation. Our preliminary results showed that HDAC inhibitors have antiangiogenesis activity and that the antitumor effects are greater when an HDAC inhibitors is combined with a vascular endothelial growth factor (VEGF) receptor inhibitor. Bevacizumab is a humanized monoclonal antibody against VEGF A. Our group has recently reported that human platelets take up bevacizumab in vitro and in vivo and thereby blocks biological activity of platelet derived VEGF. For this project our hypothesis are: 1) Hydroxamic acid HDAC inhibitors downregulate angiogenesis-related genes, inhibit tumor angiogenesis and have greater antitumor activity in combination with antiVEGF therapy; 2) Platelets represent a storage for VEGF and bevacizumab. The goal of this proposal is 1) to assess whether blockade of the HIF1a/VEGF pathway in RCC patients by SAHA will enhance the angiogenesis inhibitory activity of bevacizumab, and 2) to asses the pharmacodynamics of bevacizumab by analyzing platelet proangiogenic activity. We will pursue the following aims: Specific Aim #1: To assess the biological effects of the combination of SAHA and bevacizumab. We anticipate that the combination of SAHA and bevacizumab will have antitumor and antiangiogenesis effects in tumors with a HIF- 1a/VEGF activated pathway. We will conduct a Phase I/II study in patients with clear cell RCC and assess the pharmacodynamic effects of this combination. Specific Aim #2: To assess the angiogenic profile of isolated platelets from patients treated with the combination of SAHA and bevacizumab. These studies are significant because they represent the first step towards the development of a novel, rational, hypothesis driven, combination strategy for RCC. We aim to target HDAC inhibitors by exploiting their non- transcriptional regulation of angiogenesis related genes. The proposed research is innovative because it couples a novel therapeutic strategy targeting angiogenesis pathways in both tumor and endothelial cells. This proposal explores also novel pharmacodynamic endpoints for HDAC inhibitors and anti-VEGF based therapies for the first time. We expect that these studies will provide 1) early clinical evidence that combining HDAC inhibitors and targeted angiogenesis inhibitors increases the antitumor effects, 2) insight on the role of platelets in the pharmacodynamics of bevacizumab, and 3) the foundation for future phase II and III trials in patients with kidney cancer and other solid tumors. Our group has been interested in the development of rational combination therapies for patients with urological malignancies with the long-term goal of testing these combinations in phase II-III studies. The principal objective of the proposed research is to explore the biological interactions and therapeutic potential of the novel combination of SAHA and bevacizumab in patients with metastatic RCC. Our central hypothesis is that the combined inhibition of the VEGF pathway will have an augmented inhibitory effect on endothelial cell signaling and proliferation. To this end we will conduct a phase I/II study of SAHA in combination with bevacizumab in patients with advanced clear cell RCC. This study represents a collaborative effort. It is an investigator initiated, Cancer Therapy and Evaluation Program (CTEP) sponsored study where the clinical aspects are supported by the Johns Hopkins U01 grant. Part of the correlative studies (not included in this proposal) will be supported by the TRI mechanism and by the Cancer Imaging Branch, NCI. We are particularly well suited to conduct the proposed studies because we have assembled a team of investigators with expertise in tumor biology, drug development, biostatistics, pharmacology and imaging within the Johns Hopkins School of Medicine.

描述（由申请人提供）：肿瘤血管生成对于包括肾细胞癌（RCC）在内的上皮肿瘤的发生和进展至关重要。分化剂（例如组蛋白脱乙酰酶（HDAC）抑制剂）已被证明通过基因调节发挥其抗肿瘤作用。我们的初步结果表明，HDAC抑制剂具有抗血管生成活性，并且当HDAC抑制剂与血管内皮生长因子（VEGF）受体抑制剂组合时，抗肿瘤作用更大。贝伐单抗是一种抗VEGF A的人源化单克隆抗体。我们的小组最近报道了人血小板在体外和体内摄取贝伐单抗，从而阻断血小板衍生的VEGF的生物活性。对于该项目，我们的假设是：1）异羟肟酸HDAC抑制剂下调血管生成相关基因，抑制肿瘤血管生成，并且与抗VEGF治疗组合具有更大的抗肿瘤活性; 2）血小板代表VEGF和贝伐单抗的储存。本提案的目的是：1）评估SAHA阻断RCC患者的HIF 1a/VEGF通路是否会增强贝伐珠单抗的血管生成抑制活性; 2）通过分析血小板促血管生成活性来评估贝伐珠单抗的药效学。我们将追求以下目标：具体目标#1：评估SAHA和贝伐单抗联合治疗的生物学效应。我们预期SAHA和贝伐单抗的组合将在具有HIF- 1a/VEGF激活途径的肿瘤中具有抗肿瘤和抗血管生成作用。我们将在透明细胞肾细胞癌患者中进行I/II期研究，并评估该组合的药效学作用。具体目的#2：评估SAHA和贝伐珠单抗联合治疗患者的分离血小板的血管生成特征。这些研究意义重大，因为它们代表了为RCC开发新的、合理的、假设驱动的组合策略的第一步。我们的目标是通过利用HDAC抑制剂对血管生成相关基因的非转录调节来靶向HDAC抑制剂。这项研究具有创新性，因为它结合了一种新的治疗策略，靶向肿瘤和内皮细胞中的血管生成途径。该提案还首次探索了HDAC抑制剂和基于抗VEGF的治疗的新药效学终点。我们预计这些研究将提供1）早期临床证据，证明HDAC抑制剂和靶向血管生成抑制剂联合使用可增加抗肿瘤作用，2）了解血小板在贝伐珠单抗药效学中的作用，3）为肾癌和其他实体瘤患者的未来II期和III期试验奠定基础。我们的研究小组一直对泌尿系统恶性肿瘤患者的合理联合治疗的发展感兴趣，长期目标是在II-III期研究中测试这些组合。本研究的主要目的是探索SAHA和贝伐单抗的新型组合在转移性RCC患者中的生物学相互作用和治疗潜力。我们的中心假设是VEGF途径的联合抑制将对内皮细胞信号传导和增殖具有增强的抑制作用。为此，我们将在晚期透明细胞肾细胞癌患者中进行SAHA联合贝伐单抗的I/II期研究。这项研究是一项合作努力。这是一项由研究者发起的癌症治疗和评估项目（CTEP）申办的研究，其临床方面得到了约翰霍普金斯大学U 01基金的支持。部分相关研究（未包括在本提案中）将得到TRI机制和NCI癌症成像分支的支持。我们特别适合进行拟议的研究，因为我们在约翰霍普金斯医学院组建了一个具有肿瘤生物学、药物开发、生物统计学、药理学和成像专业知识的研究人员团队。