# Project 3: Translational Studies and Clinical Pharmacology of TLR4 and TOPK Signaling Pathway Inhibitors for Prevention of Squamous Cell Carcinoma of the Skin

> **NIH NIH P01** · UNIVERSITY OF ARIZONA · 2020 · $276,641

## Abstract

ABSTRACT
Project 3 (Curiel,Chow) Translational Studies and Clinical Pharmacology of TLR4 and TOPK Signaling
 Pathway Inhibitors for Prevention of Squamous Cell Carcinoma of the Skin
One out of three new cancers is a skin cancer, making skin cancer the most common malignancy worldwide.
Approximately 5 million cases of non-melanoma skin cancer (NMSC) occur annually in the US. Cutaneous
squamous cell carcinoma (cSCC) represents 20-25% of all NMSC. The incidence of cSCC is expected to
continue to increase as the population ages and behavioral barriers to sun protection persist. Therefore, there
is an increasing and substantial impact to society on morbidity and health care costs associated with NMSC
($8.1 billion/year) and actinic keratoses (AK) (preneoplastic cSCC lesions; > 1 billion/year).
The overall goal of this project is to determine the clinical relevance of Toll-like Receptor 4 (TLR4) and T-LAK
cell-originated protein kinase (TOPK) / p53-related protein kinase (PRPK) signaling pathways in ultraviolet light
induced human skin carcinogenesis process leading to cSCC development. Furthermore, we propose to
develop effective pharmacological small molecule inhibitors of these pathways to etsablish a personalized
medicine approach to this population in need of more effective intervention in the prevention setting. The
hypothesis for this project is that TOPK/ PRPK and TLR4 drive UV-induced carcinogenic signaling pathways in
human skin, which can be pharmacologically targeted for effective topical prevention of cutaneous cSCC. Our
approach to validate the encouraging preclinical results presented in projects 1 and 2 in chronically UV
exposed human skin includes the assessment of the activation state of these pathways in our robust archive
and prospective collection of clinically annotated matched human samples ranging from sun protected skin
(SP), sun damaged (SD), AK, to cSCC (Aim 1). The protein/phosphoprotein network architecture for TLR4 and
TOPK/PRPK will be assessed through IHC and reverse phase protein microarray (RPPA) analysis. Ultimately
we envision to identfy a subset of biomarkers by IHC that can allow us to accurately select the cohort of
patients that will benefit from a targeted intervention using one of the small molecule inhibitors proposed in this
application. To asses the modulatory effect of the proposed inhibitors in human skin we are using a
standardized acute solar simulated light (SSL) model (Aim 2). As part of this effort we will be evaluating the
effect of acute SSL exposure on the pathways of interest using SD skin (Aim 2a). Susbsequently, small
molecule inhibitors will be introduced to the acute human SSL model to determine direct targeted effects (Aim
2b). Our final aim will assess safety and phamacodynamics of the proposed TLR4 or TOPK/PRPK small
molecule inhibitors in a Phase 1 study (Aim 3).
This multidisciplinary translational proposal focuses on the novel identification of complementary cellular
signaling network an...

## Key facts

- **NIH application ID:** 10015218
- **Project number:** 5P01CA229112-02
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Clara Curiel-Lewandrowski
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $276,641
- **Award type:** 5
- **Project period:** 2019-09-10 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10015218

## Citation

> US National Institutes of Health, RePORTER application 10015218, Project 3: Translational Studies and Clinical Pharmacology of TLR4 and TOPK Signaling Pathway Inhibitors for Prevention of Squamous Cell Carcinoma of the Skin (5P01CA229112-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10015218. Licensed CC0.

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