{"content":[{"text":"Project Title: Influence of the Calorie Restricted Ketogenic diet on the Therapeutic \n Effects of 3-Bromopyruvate and JHU083 (a prodrug of 6-diazo-5- oxo-L-norleucine, DON) \n on systemic metastasis in mice.","bbox":{"left":0.117647,"top":0.091447,"width":0.7647280000000001,"height":0.04739099999999999}},{"text":"Sponsor: George W. Yu Foundation for Nutrition and Health, Incorporated \n For consideration under Grant Category 2 \n Principle Investigator: Thomas N. Seyfried, Ph.D., \n Address: Biology Department, Boston College, Chestnut Hill, MA 02467; \n Thomas.seyfried@bc.edu. \n Participating University: Boston College, 140 Commonwealth Ave., Chestnut Hill, MA 02467 \n Boston College Tax ID. 042103545.","bbox":{"left":0.117647,"top":0.155386,"width":0.7647269999999999,"height":0.11133099999999999}},{"text":"Research Project Summary \n The objective of this research to evaluate the influence of two anti-cancer drugs used alone and \n in combination with the calorie restricted ketogenic diet (KD-R) on systemic metastasis in the \n VM-M3met preclinical mouse model. The drugs include; 3-Bromopyruvate (3-BrPA) and \n JHU083 (a prodrug of 6-diazo-5- oxo-L-norleucine, DON). Both of these drugs have the ability \n to restrict ATP synthesis. No cancer can survive without energy, as we recently described (1). \n Consequently, the simultaneous targeting of glucose and glutamine metabolism becomes a \n viable therapeutic strategy for managing most cancers.","bbox":{"left":0.117647,"top":0.299022,"width":0.765064,"height":0.127392}},{"text":"Pedersen and Ko showed that 3-BrPA targets the aerobic fermentation (Warburg Effect) seen in \n most malignant tumors (2). The Warburg effect is the signature metabolic alteration seen in all \n cancers and has been linked to the unregulated growth and invasive behavior observed in most \n cancers (2-6). We have obtained preliminary evidence that 3-BrPA has anti-metastatic potential \n against our VM-M3met model when injected directly into the tumor. The glutamine analogue, \n DON, is known to target multiple glutaminases that metabolize glutamine to glutamate (7). We \n previously found that DON could reduce systemic metastasis in the VM-M3met model, but \n showed some toxicity when administered under standard dietary conditions (8). Our most \n recent findings show that a calorie restricted ketogenic diet can improve the therapeutic efficacy \n of DON while reducing toxicity (9). Recent studies also showed that the DON pro-drug \n (JHU083) could enhance tumor specific immunity by suppressing the proinflammatory activities \n of myeloid cells in mouse models of metastatic cancer (10). No prior studies have evaluated the \n therapeutic efficacy of these two anti-cancer drugs used in combination with the KD-R to \n manage metastasis in preclinical mouse models.","bbox":{"left":0.117647,"top":0.442659,"width":0.764983,"height":0.22314899999999993}},{"text":"Metastasis is the general term used to describe the spread of cancer cells from the primary \n tumor to surrounding tissues and to distant organs and is the primary cause of cancer morbidity \n and mortality (11-19). It is estimated that metastasis is responsible for about 90% of cancer \n deaths (20). This estimate has changed little in more than 50 years (21,22). Metastasis \n involves a series of sequential and interrelated steps. In order to complete the metastatic \n cascade, cancer cells must detach from the primary tumor, intravasate into the circulatory and \n lymphatic systems, evade immune attack, extravasate at distant capillary beds, and invade and \n proliferate in distant organs.(12-15,18,23,24) Metastatic cells also establish a microenvironment \n that facilitates angiogenesis and proliferation, resulting in macroscopic, malignant secondary \n tumors. Although systemic metastasis is responsible for the majority of cancer deaths, most \n research in cancer does not involve metastasis in the in vivo state (16,25). That about 1,600 \n people continue to die each day in the US from cancer, further attests to the failure in managing \n the disease once it disseminates through the body (26).","bbox":{"left":0.117647,"top":0.682356,"width":0.764942,"height":0.20708799999999994}},{"text":"1","bbox":{"left":0.872549,"top":0.938746,"width":0.009804000000000035,"height":0.01677899999999999}}],"images_bbox":[],"images_bbox_not_text_overlap":[]}