# Lymphoid Experimental Therapeutics Platform to Study Cooperative Signaling inHuman Lymphomas

> **NIH NIH R01** · GEORGIA INSTITUTE OF TECHNOLOGY · 2023 · $421,685

## Abstract

Approximately 40% of patients with activated B cell (ABC) subtype of diffuse large B cell lymphoma DLBCL
relapse or are not curable with current therapies. The mechanism through which ABC-DLBCLs are resistant to
current therapies are unknown but may be linked to the particular spectrum of somatic mutations in these
tumors, which are in concert with complex growth signals provided by the lymphoid tumor microenvironment
(Ly-TME). Many of the hallmark ABC-DLBCL mutations result in constitutive activation of B cell receptor (BCR)
and Toll like receptor (TLR) pathways in these malignant immune cells. Hence these pathways are emerging
as a source of therapeutic targets for the treatment of ABC-DLBCLs. However, to date, existing BCR pathway
inhibitors such as those targeting Bruton’s tyrosine kinase (BTK) are active in a limited subset of patients and
only for a short duration (few months), causes of which are unknown. The substantial differences in response
rates and response duration between ABC-DLBCL patients reflect the variable dependencies on BCR and TLR
signaling and/or differential regulation by the Ly-TME. Therefore, Ly-TME seems essential for ABC-DLBCLs in
spite of constitutive action of signaling pathways. ABC-DLBCLs have multiple cooperative and feed-back, and
bypass signaling pathways that promote tumor survival and personalized therapy will require combination
therapeutics to adequately suppress these networks. Unfortunately, the impact of Ly-TME on these signaling
pathways in ABC-DLBCLs and, consequently, on the efficacy of targeted therapeutics are poorly understood.
Therefore, the objective of this R01 is to develop an experimental therapeutics technology with Ly-TME and
determine the role of Ly-TME on ABC-DLBCL survival, signaling, and response to pathway inhibitors of the
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) paracaspase. By integrating
the results of R01, the team will determine the role of Ly-TME in BCR-MALT1 and TLR signaling in ABC-
DLBCL and determine a more refined dosing scheme. Mechanisms from this R01 will increase “predictive
power” of MALT1 inhibitors, and provide mechanistic clues towards resistance to MALT1 inhibitors, and
discover combinatorial therapy to overcome resistance.

## Key facts

- **NIH application ID:** 10656239
- **Project number:** 5R01CA238745-04
- **Recipient organization:** GEORGIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Ankur Singh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $421,685
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10656239

## Citation

> US National Institutes of Health, RePORTER application 10656239, Lymphoid Experimental Therapeutics Platform to Study Cooperative Signaling inHuman Lymphomas (5R01CA238745-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10656239. Licensed CC0.

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