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

摘要

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).This multidisciplinary translational proposal focuses on the novel identification of complementary cellular signaling network and their relationship with other established pathways in skin carcinogenesis, to guide the selection and early clinical development of targeted topical small molecule inhibitors. This will facilitate a personalized based approach for the therapeutic prevention of cSCC.