Sylvester Comprehensive Cancer Center

Julio C. Barredo, M.D.

Julio C. Barredo, M.D.

Professor of Pediatrics; Director, Pediatric Hematology-Oncology; Director, Sylvester Children's Cancer Programs

Description of Research

Dr. Barredo's research focuses on the molecular mechanisms leading to cancer cell sensitivity and resistance to molecular targeted agents. Using childhood acute lymphoblastic leukemia as a model, his laboratory focuses on targeting tumor metabolism and bioenergetics. His work identified AMP activated protein kinase (AMPK) as a suitable target in childhood acute lymphoblastic leukemia (ALL), and his group demonstrated that AMPK acts as a molecular regulatory switch to coordinate ALL cell fate (survival vs. death) under metabolic stress through feedback and feed-forward signaling interactions with the PI3K/Akt/mTOR and RAS signaling pathways. In this context, and due to the high prevalence of mutations and/or alteration in these oncogenes and tumor suppressor genes (PTEN, Akt, RAS pathway) in ALL, AMPK plays a prominent role in pairing energy availability and cell growth and survival in ALL cells. Through a systematic approach, his group has identified specific functional buffering interactions within these pathways that offer the opportunity for combination therapy. This is particularly important in cancer therapeutics because rarely the survival of cancer cells relies solely on the function of a single gene product or signaling protein. Therefore, targeting pathways that provide biological redundancy or functional buffering leads to increased ability to effectively target cancer cells. Based on glucose being the major source for energy in eukaryotic cells, the Barredo laboratory more recently has also investigated the regulation of glycolysis in ALL cell models.

Additional areas of interest represent the study of folate metabolism in ALL. His work has contributed to uncover the molecular mechanisms that determine the cytotoxicity of methotrexate (MTX), a universal component of childhood acute lymphocytic leukemia (ALL) therapy. His group established that the enzyme responsible for the accumulation of the active metabolites of MTX and other classical folates is regulated epigenetically and proposed a model to explain how non-random translocations present in ALL determine sensitivity of ALL to antifolates based on their ability to upregulate the accumulation of polyglutamates through the enzyme folyl-gamma-polyglutamate synthetase (FPGS). Recently they described this is an important mechanism that mediates the synergism between folate antagonists and histone deacetylase inhibitors (HDACi).

Based on pre-clinical work done by Dr. Barredo’s laboratory, tow investigator initiated clinical trials in ALL have been developed. The first is a phase I trial of the HDACi panabinostat in children with refractory/relapsed acute leukemia and lymphoma (Hodgkin’s and NHL), and the second is a trial incorporating the AMPK activator metformin to induction chemotherapy for the treatment of children and adolescents with refractory/relapsed ALL. His research is funded by the NCI, Leukemia Lymphoma Society and several other foundations.

Highlights

  • Uncovered the molecular mechanisms that control FPGS expression and accumulation of active MTX metabolites in childhood ALL phenotypes, and translated the same mechanisms into successful cooperative group clinical trials
  • Uncovered the epigenetic mechanisms regulating the expression of the gene regulating folyl-gamma-polyglutamate synthetase (FPGS)
  • Chair, national cooperative group trials for relapsed ALL
  • Identification of AMPK as a molecular target in childhood ALL, and development of strategies using the simultaneous activation of AMPK and interruption of signaling pathways of the PI3K/Akt/mTOR pathways in ALL model systems
  • Investigator initiated trials based on translation from pre-clinical laboratory studies using HDACi and AMPK activators in childhood hematological malignancies

Selected Cancer-Related Publications

  • Leclerc GM, Leclerc GJ, Kuznetsov JN, Desalvo J, Barredo JC. Metformin Induces Apoptosis through AMPK-Dependent Inhibition of UPR Signaling in ALL Lymphoblasts. PLoS One 8:e74420,2013 Read more »
  • Xi H, Barredo JC, Merchan JR, Lampidis TJ. Endoplasmic reticulum stress induced by 2-deoxyglucose but not glucose starvation activates AMPK through CaMKK? leading to autophagy. Biochem Pharmacol 85:1463-77,2013 Read more »
  • Desalvo J, Kuznetsov JN, Du J, Leclerc GM, Leclerc GJ, Lampidis TJ, Barredo JC. Inhibition of Akt Potentiates 2-DG-Induced Apoptosis via Downregulation of UPR in Acute Lymphoblastic Leukemia. Mol Cancer Res 10:969-78,2012 Read more »
  • Kuznetsov JN, Leclerc GJ, Leclerc GM, Barredo JC. AMPK and Akt Determine Apoptotic Cell Death following Perturbations of One-Carbon Metabolism by Regulating ER Stress in Acute Lymphoblastic Leukemia. Mol Cancer Ther 10:437-47,2011 [JIF 5.225] Read more »
  • Leclerc GJ, Sanderson C, Hunger S, Devidas M, Barredo JC. Folylpolyglutamate Synthetase Gene Transcription is Regulated by a Multiprotein Complex that Binds the TEL-AML1 Fusion in Acute Lymphoblastic Leukemia. Leuk Res 34:1601-9,2010 Read more »
  • Leclerc GM, Leclerc GJ, Fu G, Barredo JC. AMPK-induced activation of Akt by AICAR is mediated by IGF-1R dependent and independent mechanisms in acute lymphoblastic leukemia. J Mol Signal 5:15,2010 Read more »
  • Leclerc GJ, Mou C, Leclerc GM, Mian AM, Barredo JC. Histone deacetylase inhibitors induce FPGS mRNA expression and intracellular accumulation of long-chain methotrexate polyglutamates in childhood acute lymphoblastic leukemia: implications for combination therapy. Leukemia 24:552-62, 2010. Read more »
  • Barredo J, Ritchey AK. Controversies in the management of central nervous system leukemia. Pediatr Hematol Oncol 27:329-32,2010 Read more »

Programs

Leader of the Multidisciplinary Research Program: Molecular Oncology and Experimental Therapeutics Program

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