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

• 批准号: 10224950
• 负责人: LAURA A HANSEN
• 金额: $ 33.28万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 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/10224950
• 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; Structure; 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/antagonist; 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

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.

抽象的 非黑色素瘤皮肤癌，包括鳞状细胞癌 (SCC)，是最常见的癌症 在美国诊断的绝大多数病例是由紫外线 (UV) 引起的 辐照。鳞状细胞癌通常由癌前前体发展而来，这为干预提供了机会 预防恶性疾病和转移进展。治疗临床可检测到的恶性病变和 前驱光化性角化病仍然很大程度上依赖于手术切除。这些程序是侵入性的，带有 巨大的医疗费用，并且通常不足以预防转移进展 免疫功能低下的患者。因此，需要更有效的基于机制的治疗 没有副作用或副作用很小。在初步调查中，我们表明增加的核转运蛋白 输出蛋白 (XPO)1 驱动支架和信号蛋白 14-3-3 的异常定位以激活 SCC 细胞中的促存活途径。 14-3-3基因的遗传删除通过以下方式抑制肿瘤发展 75% 并阻止了恶性进展，而非致瘤性皮肤细胞则不受 14-3- 缺乏的影响 3。因此，我们的假设是抑制驱动异常促生存信号传导的两个关键调节因子 将提供一种新颖有效的方法来预防皮肤肿瘤的生长和恶性进展，并且以最小的速度 对周围正常皮肤的毒性。在拟议的研究中，我们将描述机制和 XPO1 驱动的异常 14-3-3 信号传导对恶性角质形成细胞的后果（目标 1），改进 我们开发的候选药物可以破坏 14-3-3 促生存信号（目标 2），并提供证据- 14-3-3 和 XPO1 抑制剂预防皮肤肿瘤发展功效的主要证据 使用人类患者来源 (PDX) 和紫外线照射诱发的皮肤癌模型进行进展和进展。 这项工作的成功完成预计将带来预防和治疗的新方法 皮肤癌。