This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Combination therapy of tumors involving transarterial particle embolization with VEGF trap administration (intra-arterially and/or systemically) will result in improved tumor destruction, decreased metastasis, and overall improved survival. BACKGROUND: Trans-arterial particle embolization has been widely investigated as a potential therapy for solid tumors, most notably hepatocellular carcinoma (HCC), liver metastases, and renal cell carcinoma.1 In this minimally invasive procedure performed using fluoroscopic guidance, the arterial supply of tumors is blocked using tiny particles, effectively eliminating the oxygen and nutrients required for tumor growth. Co-administration of chemotherapeutic agents intra-arterially results in a substantially higher intra-tumoral concentration and greatly prolongs the activity of the chemotherapeutic agent within the tumor due to the impeded blood flow. Although the theoretical benefit of tumor chemoembolization generated vast excitement at its inception, subsequent clinical trials have yielded less than impressive results due to its temporary effect and eventual tumor recurrence. Currently, embolization serves largely as a palliative therapy and second-line treatment for nonsurgical candidates as opposed to a first-line curative treatment. Substantial research has implicated increased angiogenesis as being a critical factor in tumor growth and the process of metastasis.2 One of the most prominent pro-angiogenic factors is vascular endothelial growth factor (VEGF), which is a signaling protein expressed and secreted from cells, particularly tumor cells. VEGF stimulates vascular endothelial cell growth, migration, permeability, and proliferation, which ultimately leads to angiogenesis and lymphangiogenesis. Immunohistochemical analyses of tumors in rodents and humans after embolization have demonstrated significantly increased expression of VEGF, serum VEGF levels, and angiogenesis, which have been postulated to occur secondary to the hypoxic environment caused by embolization.3-6 Increased VEGF levels have also been directly correlated with increased metastasis.7 Since angiogenesis has been well established to be a crucial process to tumor growth and metastasis, post-embolization upregulation of angiogenic factors may be responsible for treatment failure due to stimulated growth and metastasis of residual microscopic tumor. A number of anti-angiogenesis factors have been investigated for systemic use against a number of cancers, such as bevacizumab.2,8 Bevacizumab(Avastin), a monoclonal antibody that binds to VEGF to prevent activation of one of the primary VEGF receptors, is currently a first line therapy for metastatic colorectal cancer, and has also been shown to be effective against non small cell lung cancer, metastatic breast cancer, ovarian cancer, and renal cell carcinoma. Animal and preliminary studies of anti-angiogenic factors have demonstrated promise in a number of additional tumor types, including HCC. The VEGF trap (aflibercept) is a relatively recently developed soluble decoy receptor comprising parts of the VEGF receptors 1 and 2, which avidly binds VEGF and leads to potent suppression of angiogenesis at low concentrations.9 In animal models, it has been shown to block tumor growth, metastasis formation, and vascular leakage. VEGF trap is in early clinical trials and has been predicted to be superior to bevacizumab because the VEGF trap binds to a wider spectrum of the VEGF family receptors and with higher affinity. Several studies have evaluated anti-angiogenesis factors in conjunction with embolization in rodent models, although none of the therapies are directly translatable into human treatments. Additionally, the factors utilized have been shown to be inferior to VEGF antibodies in their anti-angiogenic properties.10-13 Despite this, the results of these animal studies have been promising, with resultant improved tumor destruction when these anti-angiogenic factors are co-administered with embolization. However, no animal studies have compared intra-arterial to systemic bevacizumab (or co-administration), and no studies to date have evaluated the use of the more potent VEGF trap in conjunction with embolization.
AIMS : 1. Determine whether the co-administration of the VEGF trap with particle embolization of vascular liver tumors will improve tumor destruction and decrease intrahepatic metastasis. 2. Determine which method of VEGF trap administration (intra-arterial, systemic, or both), results in maximal tumor destruction and minimal metastases when combined with particle embolization. EXPERIMENTAL DESIGN: A rat model will be utilized for the study. A tumor line with similarities to HCC will be grown within an incubator rat and sectioned into tiny pieces once adequate size has been attained (Approximately 3 weeks). From this tumor, a tiny fragment will be implanted into the liver of each experimental rat. After 2 weeks, MR imaging will be performed to measure the tumor size for each rat. Each rat will then be randomized to one of 8 groups. Since the primary goal of this study is to determine whether the co-administration of VEGF trap to trans-arterial particle embolization therapy enhances tumor destruction and metastasis, the relative control group will be rats undergoing particle embolization as the sole therapy. The primary experimental groups will also undergo particle embolization, but with concurrent intra-arterial VEGF trap administration, systemic VEGF trap administration, or both intra-arterial and systemic VEGF trap administration. However, intra-arterial and/or systemic VEGF trap administration alone may have a dominant anti-tumor effect which which is independent of particle embolization. Therefore, additional relative control groups will be required -- intra-arterial VEGF trap administration, systemic VEGF trap administration, and both, in order to clarify the contributions of VEGF administration and particle embolization. In order to understand the extent of overall tumor response compared to nontreated rats, a true control group of rats undergoing no treatment will be used.
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