# Developing novel therapy to improve outcomes in MCL

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $386,632

## Abstract

PROJECT SUMMARY
Mantle cell lymphoma (MCL) is an incurable non-Hodgkin lymphoma, and despite intensive therapeutic
approaches, the median progression-free survival after first-line treatment is four years. The emergence of
chemoresistance is rapid, durable responses to second and third-line therapies are rare, and relapse is virtually
universal in MCL. Cell cycle dysregulation, primarily by upregulation of E2F1 target genes, is a hallmark of MCL.
We identified a novel role of Fibroblast growth factor receptor-1 (FGFR1) in MCL survival and regulating cell
cycle-dependent processes primarily by inhibiting E2F1 mediated transactivation. We show that FGFR1 and not
other homologs are overexpressed in MCL patients, and its expression is associated with a poor prognosis.
Functionally, genetic ablation of FGFR1 or pharmacological targeting with erdafitinib, a selective small molecule
targeting FGFRs, induced cell cycle arrest, cell death in-vitro, reduced tumor formation, and improved overall
survival in-vivo. Mechanistically, we show that FGFR1 positively regulates E2F1-mediated transactivation of its
target gene through cMYC/EZH2/CDKN1C axis, contributing to cell survival. Hence, we hypothesize that the
FGFR1 signaling pathway is a critical modulator of cell survival and represents a novel and attractive candidate
for targeted therapy for patients with relapsed MCL. In this proposal, we will dissect the mechanisms by which
FGFR1 impacts MCL survival and perform preclinical studies using erdafitinib as a therapy to prevent and treat
MCL through the following specific aims: SA1: To characterize the role of FGFR1 in MCL survival in-vitro and in-
vivo mouse models of MCL. In this aim, we will investigate a) FGFR1's role in regulating E2F1 mediated
transactivation of target genes and survival in-vivo, b) the role of CDKN1C in regulating E2F1 dependent
transactivation program, c) the role of E2F1 target gene CDK1, to positively regulates cMYC stability and
constitute a feedback loop and d) identify mechanism-based combination strategies to maximize the therapeutic
potential of FGFR1 inhibition. SA2:To conduct a preclinical investigation of inhibition of FGFR1 using patient-
derived xenograft (PDX) murine models and a primary genetic murine model of MCL. We will conduct a
preclinical trial of erdafitinib using PDX and murine models of MCL to identify a) the doses of erdafitinib that
induce efficient inhibtion of FGFR1 signaling and downstream target gene expression without unacceptable
toxicity and b) the best dose and schedule of erdafitinib resulting in maximum clinical efficacy alone and c) in
combination with an ibrutinib. SA3: We will perform a retrospective analysis on tissue biopsies from relapsed
MCL patients to a) analyze the effects of FGFR1 protein and its associated clinical outcomes and b) analyze the
correlation between FGFR1 protein and, its activation, downstream effectors in patients with relapsed/refractory
MCL. Impact: Our proposal will est...

## Key facts

- **NIH application ID:** 10886820
- **Project number:** 5R01CA282483-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Lalit Sehgal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $386,632
- **Award type:** 5
- **Project period:** 2023-07-12 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886820

## Citation

> US National Institutes of Health, RePORTER application 10886820, Developing novel therapy to improve outcomes in MCL (5R01CA282483-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10886820. Licensed CC0.

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