Also utilize metabolic programs similar to those utilized by cancer and toxicity could be significant by targeting some metabolic pathways. For example, effector subtypes of T cells and antibody producing B cells also rely on aerobic glycolysis and glutamine metabolism to maintain immune function. Metabolic inhibition of immune cells could potentially reduce their ability to fight cancer, and further, leave patients more vulnerable to opportunistic infections. Another challenge in targeting cancer metabolism is the metabolic flexibility that many tumor cells exhibit. Except for cases where there are actual mutations in metabolic genes, cancer cells often have a remarkable ability to shift fuel sources when deprived of favored metabolic pathways. This metabolic flexibility may limit the efficacy of targeting a single pathway for therapeutic MK886 web purposes. Combination therapy as a solution One potential way to overcome the challenges posed to successfully utilize cancer metabolism as a therapeutic target is to utilize combination therapy. There are several potential ways in PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19847069 which metabolic combination therapy could be used against cancer cells. Inhibiting a primary metabolic pathway, followed by the subsequent inhibition of alternate metabolic pathways used by tumor cells might be one strategy. Additionally, many groups have shown that the partial inhibition of metabolic pathways utilized by cancer cells can dramatically sensitize the cancer cells to more traditional chemotherapeutic drugs or targeted therapies. This adjuvant metabolic sensitization may allow the use of far lower doses of both metabolic inhibitors and chemotherapeutic agents to achieve greater efficacy against tumor cells and reduced off-target effects. Conclusions The therapeutic potential of targeting the alterations of cellular metabolism in cancer has existed since the description of aerobic glycolysis by Otto Warburg. In the decades since Warburg’s observation, much progress has been made in understanding exactly how many types of 
cancer alter cellular Oleandrin web energetic pathways and how these alterations may be used to design novel therapeutic strategies to combat the disease. It is clear from recent research that there are a number of potential pathways and targets that may be beneficial targets for cancer therapy. In this review, we have described potential targets in the metabolic pathways Cancer J. Author manuscript; available in PMC 2016 March 01. Kishton and Rathmell Page 8 that regulate glycolysis, glutamine metabolism, and the TCA cycle. It is likely that research in the coming years will identify more potential targets for therapeutic intervention. While there are numerous challenges associated with targeting cancer metabolism, among them off-target effects of metabolic inhibitors and the suppression of immune cells, strategies such as using metabolic inhibitors in combination therapy may allow for more effective clinical use. Author Manuscript Author Manuscript Author Manuscript Author Manuscript Acknowledgments The authors wish to thank members of the Rathmell lab for helpful discussions during the preparation of this manuscript. This work was supported by NIH R01CA123350, NIH R03AI106835, Leukemia and Lymphoma Society, NIH F31CA183529, Duke Cancer Institute Pilot Grant. Over the last 30 years, the molecular events that drive immune responses have been characterized in great detail in numerous cell types. A successful immune response requires a delicate balance of act.Also utilize metabolic programs similar to those utilized by cancer and toxicity could be significant by targeting some metabolic pathways. For example, effector subtypes of T cells and antibody producing B cells also rely on aerobic glycolysis and glutamine metabolism to maintain immune function. Metabolic inhibition of immune cells could potentially reduce their ability to fight cancer, and further, leave patients more vulnerable to opportunistic infections. Another challenge in targeting cancer metabolism is the metabolic flexibility that many tumor cells exhibit. Except for cases where there are actual mutations in metabolic genes, cancer cells often have a remarkable ability to shift fuel sources when deprived of favored metabolic pathways. This metabolic flexibility may limit the efficacy of targeting a 
single pathway for therapeutic purposes. Combination therapy as a solution One potential way to overcome the challenges posed to successfully utilize cancer metabolism as a therapeutic target is to utilize combination therapy. There are several potential ways in PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19847069 which metabolic combination therapy could be used against cancer cells. Inhibiting a primary metabolic pathway, followed by the subsequent inhibition of alternate metabolic pathways used by tumor cells might be one strategy. Additionally, many groups have shown that the partial inhibition of metabolic pathways utilized by cancer cells can dramatically sensitize the cancer cells to more traditional chemotherapeutic drugs or targeted therapies. This adjuvant metabolic sensitization may allow the use of far lower doses of both metabolic inhibitors and chemotherapeutic agents to achieve greater efficacy against tumor cells and reduced off-target effects. Conclusions The therapeutic potential of targeting the alterations of cellular metabolism in cancer has existed since the description of aerobic glycolysis by Otto Warburg. In the decades since Warburg’s observation, much progress has been made in understanding exactly how many types of cancer alter cellular energetic pathways and how these alterations may be used to design novel therapeutic strategies to combat the disease. It is clear from recent research that there are a number of potential pathways and targets that may be beneficial targets for cancer therapy. In this review, we have described potential targets in the metabolic pathways Cancer J. Author manuscript; available in PMC 2016 March 01. Kishton and Rathmell Page 8 that regulate glycolysis, glutamine metabolism, and the TCA cycle. It is likely that research in the coming years will identify more potential targets for therapeutic intervention. While there are numerous challenges associated with targeting cancer metabolism, among them off-target effects of metabolic inhibitors and the suppression of immune cells, strategies such as using metabolic inhibitors in combination therapy may allow for more effective clinical use. Author Manuscript Author Manuscript Author Manuscript Author Manuscript Acknowledgments The authors wish to thank members of the Rathmell lab for helpful discussions during the preparation of this manuscript. This work was supported by NIH R01CA123350, NIH R03AI106835, Leukemia and Lymphoma Society, NIH F31CA183529, Duke Cancer Institute Pilot Grant. Over the last 30 years, the molecular events that drive immune responses have been characterized in great detail in numerous cell types. A successful immune response requires a delicate balance of act.