The overarching objective of the Aguiar laboratory is to improve our understanding of cancer biology, in particular the molecular and cellular basis of B cell lymphomas development and progression with the intent of translating these discoveries into clinical activities. The Aguiar laboratory uses in vitro and in vivo systems, in genome-wide or focused approaches, to investigate the pathogenesis of diffuse large B cell lymphoma (DLBCL). DLBCL is the most common B cell cancer in adults, with ~25000 new cases diagnosed yearly in the US alone. Importantly, DLBCL remains incurable in ~40% of the patients, and the last time that this suboptimal cure rate was improved, it was 20 years ago with the addition of rituximab (anti-CD20 antibody) to classical chemotherapy. Thus, the field has coalesced around the concept that to improve DLBCL outcome, we first need to better understand this disease biology, and impact on its clinical heterogeneity. Towards this end, the Aguiar group currently has three active lines of investigation: 1) the Aguiar lab is examining the interplay between mitochondrial metabolism and epigenetic modulation. In this area of knowledge, they recently made substantial contributions. First, they discovered that a subset of DLBCLs harbor loss of function mutations in D2HGDH, which encodes a mitochondrial enzyme that converts the natural metabolite D-2-HG into alpha- ketoglutarate (αKG). The main consequence of these mutations is depletion of the cellular pool of αKG and hypermethylation (DNA/RNA/histone). Subsequently, the Aguiar lab showed that MYC, a central lymphoma oncogene, regulates D2HGDH expression and thus, via modulation of intermediary metabolism, can modify the cellular epigenome. The ultimate objective of this broad research activity is to test the concept that αKG supplementation possess anti-lymphoma properties, an idea that the Aguiar lab has already validated pre-clinically. 2) The Aguiar research program is also invested in expanding and further credentialling phosphodiesterase 4 (PDE4) as an actionable therapeutic target in mature B cell malignancies. This is a long-standing research line in their group, which started with the discovery that the expression of the gene PDE4B was uniquely elevated in fatal DLBCL cases. Subsequently, in a collection of impactful publications across a decade of pre-clinical work, the Aguiar lab showed that high PDE4 expression and activity blunts the inhibitory effects of cyclic-AMP towards the B cell receptor (BCR), which thus remains abnormally active in DLBCL. The Aguiar laboratory then discovered that this oncogenic signal can be turned off with PDE4 inhibitors, a concept that they validated in two recent completed clinical trials. A third, pivotal randomized phase 2 trial has been open and will start accruing in the fall. In this study, Dr. Aguiar and his clinical co-leaders aim to confirm the benefit of adding PDE4 inhibitors to the first line treatment of DLBCL. 3) Another active r...