{"content":[{"text":"A difficulty in characterizing novel drug therapies against metastasis comes in large part from a \n dearth of animal models that show systemic metastasis involving bone marrow and multiple \n organ systems (16,25,26). The key phenotype of metastasis is that the tumor cells spread \n naturally from the primary tumor site to secondary locations. Systemic metastasis occurs for the \n VM-M3met tumor from any implantation site when grown in its natural immunocompetent and \n syngeneic VM/Dk inbred mouse host (27). Indeed, no other mouse model shows the robust \n systemic metastatic spread of cancer cells as does the VM-M3met model. The VM-M3met \n mouse tumor cells express all of the major characteristics seen in human metastatic cancer (11). \n These cells also express properties of macrophages, which are thought to represent the cellular \n origin of many human metastatic cancers (11). The VM-M3met cells are engineered to express \n a firefly luciferase (Fluc)-IRES-EGFP cassette under control of the CMV promoter (27). This \n allows in vivo tumor cell tracking using bioluminescence imaging (28). The VM-M3met model is \n ideally suited to assess the therapeutic efficacy of drugs and diets that can target systemic \n metastatic cancers. We recently demonstrated synergistic interactions between the restricted \n ketogenic diet (KD), hyperbaric oxygen therapy, OAA, and the glutamine inhibitor DON in \n reducing systemic metastasis in the VM-M3met model (9,29,30).","bbox":{"left":0.117647,"top":0.091447,"width":0.7697179999999999,"height":0.254967}},{"text":"We recently showed that the KD-R can reduce toxicity and enhance the therapeutic \n action of anti-cancer drugs (1). It is recognized that the KD-R can reduce blood \n glucose levels, while elevating blood ketones. This is interesting since many tumors are \n dependent upon glucose for growth and metastasis, but cannot use ketone bodies (b- \n hydroxybutyrate) for energy (1,31-33). Our goal is to evaluate the therapeutic efficacy \n of 3-BrPA and JHU083 when administered alone and in combination with the KD-R on \n the in vivo growth of the VM-M3met tumor cells. No information is available on the \n therapeutic efficacy of the KD-R administered with 3-BrPA or JH083 against systemic \n metastasis. The proposed research could provide evidence for a, new and powerful, \n non-toxic therapeutic strategy for managing systemic metastatic cancer. The proposed \n research will address issues related to grant category 2 involving biological, chemical, clinical, \n food science research in nutrition and its effect on disease.","bbox":{"left":0.117647,"top":0.363077,"width":0.7648059999999999,"height":0.20667000000000002}},{"text":"Specific Aims \n Aim 1 will measure the influence of 3-BrPA and JHU083 on primary tumor growth, and systemic \n metastatic spread of the VM-M3met cells. A third group will measure the influence of both drugs \n used together as a cocktail on primary tumor growth, and systemic metastatic spread of the VM- \n M3met tumor cells. Organs examined for metastasis will include; liver, lung, kidney, spleen, \n bone, and brain. In this aim, each drug will be evaluated alone and together for their ability to \n reduce metastasis.","bbox":{"left":0.117647,"top":0.590235,"width":0.7647740000000001,"height":0.11163299999999998}},{"text":"Aim 2 will determine the influence of the drug cocktail on overall survival of the mice.","bbox":{"left":0.117647,"top":0.718113,"width":0.6733709999999999,"height":0.015572999999999948}},{"text":"Experimental Design, Aim 1 \n The goal is to determine the influence of 3-BrPA and JHU083 on primary tumor growth, and \n systemic metastatic spread of the VM-M3met cells under ad libitum chow diet and restricted \n ketogenic diet. The VM-M3met cells will be implanted subcutaneously in the flank of syngeneic \n inbred VM/Dk mouse host. Termination will be determined by either moribund behavior or flank \n tumor size (no larger than 2.5 cm3), as we described previously (31,34). Tumor cell growth and \n distal invasion will be measured using bioluminescence imaging as we previously described \n (28). Food intake and body weight are monitored for approximately five days prior to tumor \n implantation. Bioluminescence imaging and tumor volume measurements will be used to","bbox":{"left":0.117647,"top":0.749932,"width":0.764824,"height":0.14345099999999988}},{"text":"2","bbox":{"left":0.872549,"top":0.938746,"width":0.009804000000000035,"height":0.01677899999999999}}],"images_bbox":[],"images_bbox_not_text_overlap":[]}