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Research
As a physician scientist, my expertise includes basic, translational research, and clinical trial design and implementation. My laboratory research focuses on tumor metabolism and exploiting the metabolic vulnerabilities of ALL lymphoblasts for therapeutic gain in relapsed/refractory childhood and adolescent & young adults with this disease and other hematological malignancies. Early work focused on one-carbon metabolism and the mechanisms that regulate the expression of FPGS as a determinant of antifolate sensitivity in ALL, and we uncovered that the lineage-specific expression of FPGS is epigenetically regulated. More recent work focuses on energy metabolism and we identified AMPK and its downstream pathways as suitable targets in acute leukemia. These efforts uncovered for the first time that ALL cells are vulnerable to the induction of cell death via ER stress/UPR mediated mechanisms.
Mechanistically we focus on the role of AMPK as a regulator of survival adaptation to energy/metabolic stress. We described a novel non-canonical role for AMPK by which it epigenetically regulates gene expression that drive survival responses to energy/metabolic stress. Our findings indicate that AMPK participates as part of a multiprotein complex on chromatin that regulates changes in gene expression. AMPKα associates with chromatin and co-localizes with Pol II across different coding and non-coding regions in the genome. Both AMPKα2 and Pol II showed distinct pattern of chromatin occupancy following energy/metabolic stress, thereby regulating gene expression and inducing a robust transcriptional gene reprogramming, including downregulation of histone gene expression. We uncovered TAF1 as a new AMPKα2 binding partner and phosphorylation substrate in regulating histone gene expression. Mechanistically, in response to energy/metabolic stress, AMPKα2 phosphorylates TAF1 at Ser-1353 to alter TAF1-Pol II interaction leading to histone gene downregulation, and other.
Several of the laboratory based discoveries by the Barredo laboratory have been translated into clinical trials, including the Children's Oncology Group and consortia such as the Pediatric Cancer Foundation/Sunshine Project. My contributions to clinical trial development and implementation include the last two national trials for children with extramedullary relapse of ALL (POG 9412, COG AALL02P2) and several multi-institutional and institutional trials including investigator initiated trials (IIT) such as a phase I trial of the HDAC inhibitor panobinostat in pediatric patients, a phase I trial of metformin in combination with induction chemotherapy for ALL, and a phase I trial of pevonedistat in addition to VXLD chemotherapy for AYA patients with relapsed/refractory ALL.