# Project 3: Targeting Tumor Metabolism in Lymphoma

> **NIH NIH P50** · UNIVERSITY OF IOWA · 2021 · $261,247

## Abstract

ABSTRACT: Project 3. A key feature of lymphomas is the glucose hypermetabolism visualized on FDG-PET 
imaging. In Project 3 (P3), we are investigating two novel drivers of glucose uptake and utilization. Our 
preliminary data have revealed that abnormal glucose uptake is a striking feature of B cells deficient in the 
signaling adaptor protein, TNFR-associated factor 3 (TRAF3). Indeed, ~30% of DLBCL samples have 
histologic evidence of TRAF3 deficiency. We also found that the multi-functional glycogen synthase kinase 
(GSK3) is increased in lymphoma cells. B cell TRAF3 in the nucleus promotes the degradation of the cAMP 
response element-binding protein (CREB) transcriptional complex, and the CREB pro-survival targets Mcl-1, 
Pim2, and c-Myc are elevated in TRAF3-deficient B cells. In addition, the CREB and NF-κB2 targets Glut1 and 
hexokinase 2 (HXK2) are also elevated in TRAF3-deficient B cells (as is glucose metabolism) and these cells 
have increased GSK3 expression. Interfering with GSK3 either by GSK3α/β knockouts that we developed or 
by inhibiting the GSK3 with a novel inhibitor 9ING-41 (Actuate Therapeutics) inhibits cell proliferation and 
induces apoptosis while sparing normal lymphocytes. Thus, there is an important link between the TRAF3 and 
GSK3 pathways that can potentially be exploited for therapeutic benefit. The overall hypothesis of P3 is that 
targeting the hyperactive metabolic pathways induced by dysregulation of key signaling pathways in lymphoma 
cells (TRAF3 deficiency; GSK3 hyperactivity) will provide a new approach to treatment that will enhance 
established therapies. We have organized this work into 3 Specific Aims. 
Aim 1. Determine how TRAF3 deficiency regulates survival and glucose metabolism in pre-malignant 
 and malignant B cells. 
Aim 2: Determine the mechanism of action of GSK3 inhibitors in lymphoma cells to develop rational 
 combinations for clinical trials. 
Aim 3: Conduct clinical trials of novel inhibitors of tumor metabolism in patients with relapsed 
lymphoma. 
P3 is addressing a significant unmet need in lymphoma biology and therapeutics – understanding and 
targeting the pathways and mechanisms of the increased glucose metabolism that characterizes almost all 
aggressive lymphomas at diagnosis and those tumors that fail initial therapy and become refractory. We are 
approaching this problem in lymphoma biology and treatment with a team experienced in the study of 
lymphoma biology, signal transduction pathway analysis and clinical trials experience with signal transduction 
pathway inhibitors. Within the 5 years of this Project we aim to translate new biomarkers and therapies to our 
patients with glucose-avid lymphomas and spur new research into this important area.

## Key facts

- **NIH application ID:** 10208779
- **Project number:** 5P50CA097274-20
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** GAIL A. BISHOP
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $261,247
- **Award type:** 5
- **Project period:** 2002-09-11 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10208779

## Citation

> US National Institutes of Health, RePORTER application 10208779, Project 3: Targeting Tumor Metabolism in Lymphoma (5P50CA097274-20). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10208779. Licensed CC0.

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