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. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]