# Investigating Bruton's Tyrosine Kinase Dependency in Primary Central Nervous System Lymphoma

> **NIH NIH F31** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $45,520

## Abstract

Project Summary/Abstract
Primary central nervous system lymphoma (PCNSL) is an aggressive disease that presents solely in the
central nervous system (CNS). Due to its low disease incidence and the poor quality of patient samples, it has
very been challenging to establish preclinical disease models of PCNSL. Therefore, a majority of the
knowledge we currently have regarding PCNSL biology and pathogenesis is based on sequencing studies in
small patient cohorts, particularly gene expression studies and mutation profiling. Based on gene expression
studies, most PCNSL is categorized as diffuse large B cell lymphoma (DLBCL), the most common form of
Non-Hodgkin lymphoma. Of the three DLBCL subtypes, PCNSL most resembles the activated B cell-like (ABC)
subtype. Based on mutation profiling of PCNSL tumors, PCNSL has recurrent mutations in myeloid
differentiation primary response gene 88 (MYD88) (70%) and cluster of differentiation 79B (CD79B) (40%).
MYD88 is an adaptor protein associated with Toll-like receptor (TLR), while CD79B is a molecule required for
B cell receptor (BCR) signaling. MYD88 and CD79B mutations are also found in ABC DLBCL, though not to
the same frequencies as in PCNSL. These mutations are associated with increased activation of nuclear factor
kappa-light-chain enhancer of activated B cells (NF-κB) in PCNSL. Several targeted therapies have been
developed to inhibit this pathway and one example (the first in class) is ibrutinib, a Bruton's Tyrosine Kinase
(BTK) inhibitor.
BTK is a central signaling node downstream of BCR and TLR. BTK inhibition with ibrutinib has recently been
FDA approved for the treatment of several B cell malignancies. Our Phase I/II clinical trial at Memorial Sloan
Kettering Cancer Center in relapsed or refractory CNS lymphoma showed that 75% of patients responded to
ibrutinib. Though this may appear to simply be a B cell lineage addiction to BTK, we think this is unlikely
because some B cell malignancies actually do not respond to ibrutinib. Moreover, of the study patients who
responded to ibrutinib, some had mutations in MYD88 and/or CD79B while others did not, indicating that
MYD88/CD79B mutation status is insufficient to explain the ibrutinib response. We therefore hypothesize that
PCNSL has an overall dependency on BTK that is not due to a B cell lineage addiction. In the proposal, we aim
to understand the BTK dependency of PCNSL by assessing the relationship between BTK activation and
ibrutinib response in our novel preclinical disease models, determining the effect of the microenvironment on
BTK dependency, and exploring mechanisms of ibrutinib resistance and combination therapies to overcome
resistance. Our overall goal is to further understand the role of BTK in the PCNSL response to ibrutinib, so that
we can take steps to augment the positive results we have seen in patients.

## Key facts

- **NIH application ID:** 9981686
- **Project number:** 5F31CA220985-04
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Sarah Tang
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2017-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981686

## Citation

> US National Institutes of Health, RePORTER application 9981686, Investigating Bruton's Tyrosine Kinase Dependency in Primary Central Nervous System Lymphoma (5F31CA220985-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9981686. Licensed CC0.

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