Targeting Tumor Angiogenesis with SAHA and Bevacizumab in Kidney Cancer

描述(申请人提供)：肿瘤血管生成对包括肾细胞癌(RCC)在内的上皮性肿瘤的发展和进展至关重要。分化药物，如组蛋白脱乙酰酶(HDAC)抑制剂，已被证明通过基因调控发挥其抗肿瘤作用。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)受体抑制剂联合使用时，其抗肿瘤作用更强。贝伐单抗是一种人源化的抗血管内皮生长因子A的单抗，我们的研究小组最近报道，人的血小板在体外和体内结合贝伐单抗，从而阻断血小板来源的血管内皮生长因子的生物学活性。对于这个项目，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，与抗血管内皮生长因子治疗联合使用具有更强的抗肿瘤活性；2)血小板代表血管内皮生长因子和贝伐单抗的储存。本研究的目的是：1)评价SAHA阻断肾癌患者HIF1a/VEGF通路是否能增强贝伐单抗的血管生成抑制作用；2)通过分析血小板促血管生成活性来评价贝伐单抗的药效学。我们将追求以下目标：具体目标1：评估SAHA和贝伐单抗联合的生物学效应。我们预计SAHA和贝伐单抗在HIF-1a/VEGF激活途径的肿瘤中将具有抗肿瘤和抗血管生成的作用。我们将在透明细胞肾癌患者中进行一项I/II期研究，并评估这种组合的药效学效果。具体目标#2：评估联合应用SAHA和贝伐单抗治疗的患者的分离血小板的血管生成情况。这些研究意义重大，因为它们代表着为RCC开发一种新的、理性的、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控来靶向它们。这项拟议的研究具有创新性，因为它结合了一种新的治疗策略，针对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抑制剂和抗血管内皮生长因子治疗的新的药效学终点。我们期望这些研究将提供：1)结合HDAC抑制剂和定向血管生成抑制剂可增强抗肿瘤作用的早期临床证据；2)深入了解血小板在贝伐单抗药效学中的作用；3)为未来针对肾癌和其他实体肿瘤患者的II期和III期试验奠定基础。我们小组一直对为泌尿系恶性肿瘤患者开发合理的联合疗法感兴趣，长期目标是在II-III期研究中测试这些联合疗法。拟议研究的主要目的是探索SAHA和贝伐单抗的新组合在转移性肾癌患者中的生物相互作用和治疗潜力。我们的中心假设是，联合抑制血管内皮生长因子通路将对内皮细胞信号和增殖产生增强的抑制作用。为此，我们将进行SAHA联合贝伐单抗治疗晚期透明细胞肾癌患者的I/II期研究。这项研究代表了一项合作努力。这是一项由研究人员发起的癌症治疗和评估计划(CTEP)赞助的研究，其临床方面得到了约翰霍普金斯大学U01拨款的支持。部分相关研究(不包括在本提案中)将得到TRI机制和NCI癌症成像分部的支持。我们特别适合进行拟议的研究，因为我们在约翰·霍普金斯医学院内部组建了一支拥有肿瘤生物学、药物开发、生物统计学、药理学和成像专业知识的研究团队。

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.