Metabolic Disruption

Explaining Metabolic Disruption Technology ("MDT")

A growing body of research indicates that interfering with cell metabolism is the key to targeting cancer cells. The way a cell metabolizes its sources of energy appears to determine whether it will survive the most common treatments for cancer--chemotherapy and radiation. Cells that rely on glucose (or sugar) for fuel are easily damaged and killed. Cells that can run on fat can become deadly. They continue to survive and even thrive during cancer treatments--thereby assisting in the development of drug resistant tumors that can become lethal to their victims.

Every cell in the body produces, consumes, and stores energy using a distinct metabolic strategy to perform its normal functions. Each cell can use carbohydrate, protein, or fat in different proportions to insure that the cell has sufficient energy. The cell’s choice of fuel, i.e. the cell’s metabolic strategy, will change depending on its activation or differentiation state as well as its environment. For example, a cell that is dividing has different energy demands than one that is non-dividing and, thus, must employ an alternative metabolic strategy. Because, in general, cancer cells grow very rapidly, cancer cells have very high energy demands. We have learned that some of the mechanisms the tumor cells use to meet their energy demands are unique to the tumor cell and are not used by normal cells, suggesting that those specific pathways could make clinically relevant therapeutic targets. As a result, our work now indicates that when the tumor cells’ specific energy strategies are interrupted with “metabolic disrupting” agents, the consequences are two-fold: the cancer cells can no longer generate energy needed to survive and the disruption of the intracellular energy levels reduces their ability to repair damage from other cytotoxic agents, resulting in a much greater sensitivity to chemotherapy and radiation.

Tumor cells exhibit at least two generalizeable metabolic features that we have chosen as selective targets, high rate glycolysis (the process of breaking down glucose to smaller carbon-containing units in the cytosol of the cell) and fatty acid oxidation (the process of breaking fats down to smaller carbon containing units in the cell’s powerhouse, the mitochondria). The preferential use of fatty acid oxidation in the mitochondria of drug resistant cells is a particularly important focus of our therapeutic strategy because drug resistance, either acquired through drug treatment or inherent drug resistance, is the leading cause of death for cancer patients. For all of these reasons, our initial clinical compounds are comprised of pharmaceutical compositions that interfere with various aspects of high rate glycolysis and fatty acid oxidation. These include (but are not limited to) dichloroacetate (DCA), etomoxir and 2-deoxyglucose (2-DG).

DCA is an orally-active small molecule drug that inhibits certain aspects of high rate glycolysis and fatty acid metabolism. DCA is very close in structure to an essential intermediate in glucose metabolism, the molecule pyruvate. By mimicking the effects of pyruvate, DCA likely acts in two capacities: first, to function as an inhibitor of high rate glycolysis by sending the cell the message that nutrient reserves are full and second, to interfere with pyruvate dehydrogenase kinase, an enzyme involved in the mitochondrial switch to fatty acid oxidation under conditions of starvation. The second line of our approach involves two other metabolic inhibitors known as etomoxir and 2-DG, which are also orally-active small molecules that selectively block distinct aspects of fatty acid oxidation and glucose/carbohydrate metabolism respectively. Our research indicates that they are capable of interfering with the metabolic strategy of both drug sensitive and multi-drug resistant tumor cells. The choice of these two compounds is the result of elucidating the two distinct metabolic characteristics of drug resistant tumor cells. Preliminary studies both in vitro and in tumor bearing mice have demonstrated a lack of toxicity and impressive therapeutic activity of etomoxir in multi-drug resistant cancer cells and an even more potent combined effect with 2-deoxyglucose on both drug sensitive and drug resistant tumor cells. In addition, these two compounds have striking therapeutic activity in tumor-bearing mice when used together, or in conjunction with, standard chemotherapy.

Through the use of these compounds and others with similar activities, our portfolio of metabolic disrupting agents include agents that disrupt high rate glycolysis, agents that interfere at various control points in fatty acid oxidation and the use of either or both of these categories of metabolic disrupting agents in combination with conventional chemotherapeutic agents to reverse drug resistance. The Company has planned a clinical trial of etomoxir and 2-deoxyglucose on drug-resistant glioblastoma patients under an Investigator’s Investigational New Drug (IND) Application with the FDA for January 2011.

We established a subsidiary called MetaCytoLytics to investigate these agents and several other novel compounds in wound healing (since it too is characterized by proliferating cells). A second, separate subsidiary called VG Energy is researching the use of metabolic disruption agents to enhance the fatty acid content of plants for yield enhancement of plant oils including biofuels.

Visit: MetaCytoLytics and VG Energy, Inc. to learn more.