# Identify the Mechanisms of LMO2-Mediated Inhibition of Homologous Recombination and Establish PARP-Targeted Synthetic Lethality as a New Therapy for DLBCL

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2023 · $352,286

## Abstract

PROJECT SUMMARY/ ABSTRACT
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), with
~25,000 new cases yearly. Despite marked improvement in therapy, about half of these patients succumb to
their disease. Therefore, there is a strong need for new therapeutic approaches to improve DLBCL patients'
survival. Here we show that in DLBCL cells the LIM domain-only 2 (LMO2) protein inhibits DNA double-strand
break (DSB) repair via homologous recombination (HR), resulting in HR-dysfunction. This HR-dysfunction
phenocopies BRCA1/2 mutations in breast, ovarian and castration-resistant prostate cancers. Accordingly, we
show that LMO2 predisposes DLBCL cells to synthetic lethality upon treatment with Poly(adenosine
diphosphate
ribose)
polymerase
1
and
2
(PARP1/2)
inhibitors. The long-term goal is to demonstrate that
PARPi activity may improve outcome of patients with LMO2 expressing DLBCL. The overall objectives of this
proposal are to determine the mechanisms by which LMO2 inhibits the repair of DNA breaks via HR and
whether LMO2 expression levels can be exploited as a biomarker for sensitivity of DLBCL to PARP1/2
inhibitors. The central hypothesis is that inhibition of DNA repair via HR induced by LMO2 will sensitize DLBCL
tumors to PARP1/2 inhibitors. The rationale for this project is that deficiency in HR and failure
to
repair
DSBs
produced
cause
solid
during replication Indeed, PARP1/2 inhibitors that
the accumulation of toxic DSBs during replication, had been exploited for the treatment of HR-deficient
tumors.
can lead to genomic instability and/or cell death.
Our preliminary data showed that in DLBCL cells LMO2 inhibits the HR pathway. Thus, we
propose that inhibition of HR by LMO2 will sensitize DLBCL tumors to PARP1/2
inhibitors.
In
order
to
test
the
central
aims :
hypotesis and determine the mechanims by which LMO2 controls DNA repair we propose three specific
1)Identify mechanism(s) of LMO2-mediated inhibition of HR in DLBCL; 2) Determine how LMO2 affects
immunoglobulin class switch recombination in normal B-cells; and 3) Demonstrate that DLBCL expressing
LMO2 are sensitive to PARP1/2 inhibition. The proposed research is innovative because it represents a
substantive departure from the current status quo by demonstrating that expression of LMO2 protein predicts
therapeutic activity of PARP1/2 inhibitors in DLBCL and represents an effective new therapeutic strategy that
will broaden the existing arsenal against this lymphoma. The research proposed is significant because it is
expected to provide strong scientific justification for the development of a novel therapeutic approach for
DLBCL based in PARP1/2 inhibitors that could potentially change the current treatment of DLBCL patients and
improve their outcome.

## Key facts

- **NIH application ID:** 10599232
- **Project number:** 5R01CA233945-05
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** IZIDORE S LOSSOS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $352,286
- **Award type:** 5
- **Project period:** 2019-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10599232

## Citation

> US National Institutes of Health, RePORTER application 10599232, Identify the Mechanisms of LMO2-Mediated Inhibition of Homologous Recombination and Establish PARP-Targeted Synthetic Lethality as a New Therapy for DLBCL (5R01CA233945-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10599232. Licensed CC0.

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