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Targeting aberrant anti-apoptotic signaling for prevention of skin cancer

针对异常抗凋亡信号传导预防皮肤癌

基本信息

批准号：
10400726
负责人：
LAURA A HANSEN
金额：
$ 32.62万
依托单位：
CREIGHTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10400726
关键词：
Apoptosis Apoptotic Benign Binding CDC25A gene Cancer Model Carrier Proteins Cell Death Cell Nucleus Cells Cessation of life Client Clinical Treatment Clinical Trials Cytoplasm Data Dependence Development Dimerization Disease Dose Excision Exportins Gene Deletion Genes Genetic Growth Health Care Costs Heterodimerization Human Immunocompromised Host Incidence Intervention Investigation Knockout Mice Lead Lesion Libraries Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Malignant Squamous Cell Minor Mus Nuclear Oncogenic Operative Surgical Procedures Organ Transplantation PTPRJ gene Pathway interactions Patients Penetration Peptides Population Prevention Prevention approach Procedures Proteins Proto-Oncogene Proteins c-akt Recurrence Regulation Research Scaffolding Protein Signal Pathway Signal Transduction Signaling Protein Skin Skin Cancer Skin Carcinogenesis Skin Carcinoma Skin Neoplasms Solid Squamous cell carcinoma Survival Rate Testing Toxic effect Translating Tumor Suppressor Proteins UV Radiation Exposure United States Work Xenograft procedure anti-cancer base cancer cell cancer diagnosis cancer therapy cell killing design efficacy evaluation experimental study immunosuppressed improved in silico inhibitor keratinocyte molecular dynamics mortality novel novel strategies nucleocytoplasmic transport overexpression premalignant prevent side effect skin cancer prevention survivin targeted agent tumor tumor growth tumor progression ultraviolet ultraviolet irradiation

项目摘要

ABSTRACT Nonmelanoma skin cancer, which includes squamous cell carcinoma (SCC), is the most common cancer diagnosed in the United State,s with the overwhelming majority of cases resulting from ultraviolet (UV) irradiation. SCC usually develop from premalignant precursors, providing an opportunity for intervention to prevent malignant disease and metastatic progression. Treatment of clinically detectable malignant lesions and precursor actinic keratoses still relies largely on surgical excision. These procedures are invasive, carry a significant healthcare cost, and are often an insufficient means of preventing metastatic progression in immunocompromised patients. Consequently, there is a need for more effective mechanism-based treatments with no or minor side effects. In preliminary investigations, we showed that increased nuclear transporter exportin (XPO)1 drives aberrant localization of the scaffolding and signaling protein 14-3-3 to activate prosurvival pathways in SCC cells. Genetic deletion of the gene for 14-3-3 suppressed tumor development by 75% and blocked malignant progression while nontumorigenic skin cells were unaffected by the lack of 14-3- 3. Consequently, our hypothesis is that inhibiting two key regulators that drive aberrant prosurvival signaling will provide a novel and effective means to prevent skin tumor growth and malignant progression with minimal toxicity to the surrounding normal skin. In the proposed research we will delineate the mechanisms and consequences of XPO1-driven aberrant 14-3-3 signaling for malignant keratinocytes (Aim 1), improve upon candidate agents we have developed that disrupt 14-3-3 prosurvival signaling (Aim 2), and provide proof-of- principle evidence of the efficacy of 14-3-3 and XPO1 inhibitors for the prevention of skin tumor development and progression using human patient derived (PDX) and UV irradiation-induced skin cancer models. Successful completion of this work is anticipated to lead to novel approaches for the prevention and treatment of skin cancer.

摘要