# Targeting the Unique Paracaspase MALT1 to Overcome Ibrutinib Resistance in Relapsed/Refractory MCL Patients

> **NIH NIH R21** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $227,205

## Abstract

SUMMARY
Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy that is not yet curable. Both as monotherapies
and in combination, the Bruton's tyrosine kinase inhibitor ibrutinib and the BH3 mimetic BCL2 inhibitor venetoclax
have proven to be effective treatment options for MCL. However, only 21% of patients who received
monotherapies ibrutinib or venetoclax and 71% of patients who received the combined therapy achieved a
complete response. Furthermore, mono- and dual resistance frequently develops. Therefore, there is an urgent
unmet need to overcome resistance to these agents and to study alternative treatment options. Constitutive NF-
κB activation is a hallmark of MCL. Indeed, next generation sequencing analysis of 110 MCL patient samples
revealed that genes in the NF-κB signaling pathway had the highest mutation rate (29%), indicating the significant
contribution of NF-κB signaling to ibrutinib resistance in MCL. Through whole transcriptomic sequencing, we
showed that mucosa-associated lymphoid tissue transformation protein (MALT1) is overexpressed and
hyperactive in ibrutinib-resistant and ibrutinib-venetoclax dual-resistant MCL cells. MALT1 is a unique
paracaspase within the human genome, and it plays a crucial role in NF-κB signaling, suggesting that MALT1
may be a potential therapeutic target to overcome ibrutinib resistance and ibrutinib-venetoclax dual-resistance
without significant off-target side effects. Indeed, MI-2, a MALT1 inhibitor, has been shown to selectively target
MALT1 in activated B-cell-like diffuse large B-cell lymphoma and chronic lymphocytic leukemia. Our preliminary
data show that MI-2 is highly potent in killing ibrutinib-resistant and ibrutinib-venetoclax dual-resistant MCL cells.
To address the underlying mechanisms by which MALT1 contributes to therapeutic resistance and how targeting
MALT1 can overcome ibrutinib resistance and ibrutinib-venetoclax dual resistance, we aim to 1) determine the
efficacy of MI-2 as a single agent or in combination with other agents in MCL cell lines, primary MCL patient
samples, and PDX models in vitro; 2) characterize MALT1-mediated mechanisms underlying MCL disease
progression and ibrutinib-venetoclax resistance by introducing MALT1 clinical mutants into MCL cells in vitro;
and 3) determine the efficacy of targeting MALT1 alone or with other target(s) to overcome ibrutinib-venetoclax
resistance in vivo using MCL PDX mouse models. Successful completion of the proposed study will provide
strong evidence demonstrating the role of MALT1 in MCL malignancy and therapeutic resistance and how
targeting the unique paracaspase MALT1 may overcome ibrutinib resistance and ibrutinib-venetoclax dual
resistance, ultimately leading to clinical strategies to treat ibrutinib and/or venetoclax-refractory/relapsed MCL
patients.

## Key facts

- **NIH application ID:** 9877088
- **Project number:** 1R21CA237969-01A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Vivian Jiang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $227,205
- **Award type:** 1
- **Project period:** 2019-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9877088

## Citation

> US National Institutes of Health, RePORTER application 9877088, Targeting the Unique Paracaspase MALT1 to Overcome Ibrutinib Resistance in Relapsed/Refractory MCL Patients (1R21CA237969-01A1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9877088. Licensed CC0.

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