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

> **NIH NIH P01** · UNIVERSITY OF ARIZONA · 2022 · $234,461

## Abstract

ABSTRACT
Project 3 (Curiel) Translational Studies and Clinical Pharmacology of TLR4 and TOPK
 SignalingPathway 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 lightinduced human skin
carcinogenesis process leading to cSCC development. Furthermore, we propose to develop effective
pharmacological small molecule inhibitors of these pathways to establish 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 inhuman 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 network architecture for TLR4 and TOPK/PRPK will be assessed through
immunohistochemistry and reverse phase protein microarray (RPPA) analysis for alterations in
protein/phosphoprotein expression, and spatial RNA analysis using the Nanostring GeoMx DSP platform for
transcriptomic changes. Ultimately,we envision to identify a subset of biomarkers 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 thisapplication. To assess 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). Subsequently,
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).Th...

## Key facts

- **NIH application ID:** 10410014
- **Project number:** 3P01CA229112-03S2
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Clara Curiel-Lewandrowski
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $234,461
- **Award type:** 3
- **Project period:** 2019-09-10 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10410014

## Citation

> US National Institutes of Health, RePORTER application 10410014, Project 3: Translational Studies and Clinical Pharmacology of TLR4 and TOPK Inhibitors for Prevention of Squamous Cell Carcinoma of the Skin (3P01CA229112-03S2). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10410014. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*