# BLRD Research Career Scientist Award Application

> **NIH VA IK6** · SOUTH TEXAS VETERANS HEALTH CARE SYSTEM · 2024 · —

## Abstract

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...

## Key facts

- **NIH application ID:** 10921726
- **Project number:** 1IK6BX006542-01
- **Recipient organization:** SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
- **Principal Investigator:** Ricardo C Aguiar
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-04-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10921726

## Citation

> US National Institutes of Health, RePORTER application 10921726, BLRD Research Career Scientist Award Application (1IK6BX006542-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10921726. Licensed CC0.

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