# Targeting p38 gamma signaling to advance Cutaneous T Cell Lymphoma Therapy

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2020 · $691,849

## Abstract

Cutaneous T cell lymphoma (CTCL) is a disfiguring, incurable cancer. For patients with advanced disease,
current therapies are inadequate, and outcome is poor. An incomplete understanding of CTCL molecular
regulators has limited development of effective targeted therapies. One candidate regulator is p38γ, the gene
expression of which is selectively increased in CTCL cell lines and patient samples, but not healthy T cells. We
demonstrate that inhibition or silencing of p38γ inhibits proliferation and induces CTCL cell death. The NF-κB
pathway is constitutively active in CTCL, provides a complementary T cell signaling pathway to p38γ, and can
be inhibited by histone deacetylase inhibitors (HDACi). HDACi, which are currently the most effective clinically
approved cytotoxic compounds against CTCL, demonstrate synergistic killing when combined with p38γ
Inhibition. Our objective is to understand and exploit the p38γ pathway in CTCL, using a combination of
molecular, chemical, and genetic approaches. Our first Aim is to determine the mechanisms by which p38γ
inhibition induces cell death in CTCL. We will define the kinase cascade involved in p38γ inhibition-induced
CTCL cell killing and identify phosphorylation targets of p38γ signaling; use a synthetic lethal RNAi screen to
identify signaling components that cause cell death upon depletion in the presence of p38γ inhibition; and
determine the extent to which combined inhibition of p38γ and complementary pathways, including HDACs,
induce synergistic therapeutic effects. We will validate identified proteins for the ability to affect downstream
signaling and cellular responses in vitro and in vivo, using CTCL cell line xenograft and patient-derived xenograft
(PDX) models. Our second Aim is to develop novel p38γ inhibitors for potential therapeutic application. Using
high throughput screening and molecular modeling, we identified the multi-kinase inhibitor F7 (also known as
PIK75), and showed it is an ATP-competitive p38γ inhibitor with nanomolar cytotoxic efficacy against CTCL cells.
To develop a more selective p38γ inhibitor, we will combine ligand- and structure-based computational methods
with organic synthesis; using F7 as a scaffold molecule, we will identify F7 analogs and derivatize F7 to have
higher a binding affinity for p38γ than other kinases. In addition, we will use CRISPR-based screening to identify
novel functional domains and non-conserved sites for developing allosteric next-generation therapeutics. We will
synthesize the various analogs and validate hits for CTCL cytotoxicity and p38γ-specific kinase inhibition in vitro
and in vivo, using CTCL xenograft and PDX models. We expect that successful completion of this proposal will
yield mechanistic information about the unique biological and clinical relevance of p38γ signaling and
complementary pathways in CTCL. Importantly, validation of a specific p38γ inhibitor with efficacy in CTCL
animal models will have immediate relevance for CTCL t...

## Key facts

- **NIH application ID:** 9828624
- **Project number:** 5R01CA233922-02
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** STEVEN Terry ROSEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $691,849
- **Award type:** 5
- **Project period:** 2018-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828624

## Citation

> US National Institutes of Health, RePORTER application 9828624, Targeting p38 gamma signaling to advance Cutaneous T Cell Lymphoma Therapy (5R01CA233922-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9828624. Licensed CC0.

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