S models. Similarly, aminooxyacetate, a non-specific aminotransferase inhibitor, has demonstrated efficacy in xenograft models. However, it has not been established whether target effects or off-target effects of these compounds were responsible for their antitumor activity, and their clinical development has been suspended. Addressing glycolysis via LDH-A LDH controls the rate-limiting final step of glycolysis, converting pyruvate into lactate in the cytoplasm. LDH activity is not required in normal tissues under normoxic conditions. The two LDH isoforms can be combined as five different tetramers. LDH-A is predominantly expressed in the liver and muscles and LDH-B in the myocardia. LDH-5 is composed of four LDH-A units which is overexpressed in many cancers including PDAC as a result of post-translational or transcriptional c-Myc, K-Ras, HIF-1, and FOXM1 dependent regulation, and is associated with poor prognosis. In vitro and in vivo constitutive expression of LDH-A enhances cell growth while its silencing decreases tumorigenicity of PDAC cells. Several LDH-5 inhibitors are in preclinical development but their efficacy in vivo is limited by their pharmacokinetic profile warranting optimization of their structure/ stability and/or administration modalities. Interestingly, an LDH-A genetic deficiency causes myopathy only PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19861655 after major physical effort and individuals carrying this anomaly are 
healthy, suggesting that LDH-5 inhibition would present limited toxicities. Enhancing asparagine deprivation with L-asparaginase L-asparaginase catalyzes the hydrolysis of asparagine into aspartic acid and ammonia, inducing asparagine deprivation. L-asparaginase is one of the most efficient agents against acute lymphoblastic leukemia, being used in the clinic for almost 50 years. Leukemic lymphoblasts exhibit very low levels of ASNS – as do PDAC cells meaning they are unable to produce de novo asparagine and these cells thus rely on exogenous supplementation. L-asparaginase-induced asparagine deprivation triggers cell apoptosis, and in vitro and in vivo experiments show that PDAC cells expressing low ASNS are very sensitive to L-asparaginase. Interestingly, asparagine depletion may be rescued by glutamine through a transamidation reaction catalyzed by ASNS; asparaginase anti-leukemic activity correlated strongly with asparaginase-induced glutamine reduction, eventually resulting in protein synthesis inhibition and initiation of autophagy. 16837 Oncotarget Blocking lactate PP 242 cost transport Lactate efflux plays a critical role in intracellular pH regulation and in tumor-stroma interactions contributing to cancer cell invasiveness and immune escape. Lactate transport occurs via monocarbonate transporters: MCT-4 for lactate efflux of highly glycolytic cells, and MCT-1 for lactate import into cells that use lactate as www.impactjournals.com/oncotarget The classically formulated L-asparaginase is limited by toxicity and development of an immune response. A new formulation encapsulating L-asparaginase in erythrocytes has increased bioavailability and a better toxicity profile while retaining strong antitumor activity in leukemia. Based on preclinical data showing activity, a phase II clinical trial in PDAC with this formulation as second-line therapy is ongoing in the PDAC metastatic setting. Regulating fatty acid synthesis Two widely used drugs, metformin and statins, provide evidence that targeting lipid metabolism in cancer may have Roscovitine therapeutic efficacy. Metfor.S models. Similarly, aminooxyacetate, a non-specific aminotransferase inhibitor, has demonstrated efficacy in xenograft models. However, it has not been established whether target effects or off-target effects of these compounds were responsible for their antitumor activity, and their clinical development has been suspended. Addressing glycolysis via LDH-A LDH controls the rate-limiting final step of glycolysis, converting pyruvate into lactate in the cytoplasm. LDH activity is not required in normal tissues under normoxic conditions. The two LDH isoforms can be combined as five different tetramers. LDH-A is predominantly expressed in the liver and muscles and LDH-B in the myocardia. LDH-5 is composed of four LDH-A units which is overexpressed in many cancers including PDAC as a result of post-translational or transcriptional c-Myc, K-Ras, HIF-1, and FOXM1 dependent regulation, and is associated with poor prognosis. In vitro 
and in vivo constitutive expression of LDH-A enhances cell growth while its silencing decreases tumorigenicity of PDAC cells. Several LDH-5 inhibitors are in preclinical development but their efficacy in vivo is limited by their pharmacokinetic profile warranting optimization of their structure/ stability and/or administration modalities. Interestingly, an LDH-A genetic deficiency causes myopathy only PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19861655 after major physical effort and individuals carrying this anomaly are healthy, suggesting that LDH-5 inhibition would present limited toxicities. Enhancing asparagine deprivation with L-asparaginase L-asparaginase catalyzes the hydrolysis of asparagine into aspartic acid and ammonia, inducing asparagine deprivation. L-asparaginase is one of the most efficient agents against acute lymphoblastic leukemia, being used in the clinic for almost 50 years. Leukemic lymphoblasts exhibit very low levels of ASNS – as do PDAC cells meaning they are unable to produce de novo asparagine and these cells thus rely on exogenous supplementation. L-asparaginase-induced asparagine deprivation triggers cell apoptosis, and in vitro and in vivo experiments show that PDAC cells expressing low ASNS are very sensitive to L-asparaginase. Interestingly, asparagine depletion may be rescued by glutamine through a transamidation reaction catalyzed by ASNS; asparaginase anti-leukemic activity correlated strongly with asparaginase-induced glutamine reduction, eventually resulting in protein synthesis inhibition and initiation of autophagy. 16837 Oncotarget Blocking lactate transport Lactate efflux plays a critical role in intracellular pH regulation and in tumor-stroma interactions contributing to cancer cell invasiveness and immune escape. Lactate transport occurs via monocarbonate transporters: MCT-4 for lactate efflux of highly glycolytic cells, and MCT-1 for lactate import into cells that use lactate as www.impactjournals.com/oncotarget The classically formulated L-asparaginase is limited by toxicity and development of an immune response. A new formulation encapsulating L-asparaginase in erythrocytes has increased bioavailability and a better toxicity profile while retaining strong antitumor activity in leukemia. Based on preclinical data showing activity, a phase II clinical trial in PDAC with this formulation as second-line therapy is ongoing in the PDAC metastatic setting. Regulating fatty acid synthesis Two widely used drugs, metformin and statins, provide evidence that targeting lipid metabolism in cancer may have therapeutic efficacy. Metfor.