Targeting aberrant anti-apoptotic signaling for prevention of skin cancer

摘要 非黑色素瘤皮肤癌，包括鳞状细胞癌（SCC），是最常见的癌症 在美国确诊的病例中，绝大多数病例是由紫外线（UV）引起的。 辐照SCC通常由癌前病变发展而来，为干预提供了机会， 预防恶性疾病和转移性进展。治疗临床可检测的恶性病变， 前体光化性角化病仍然主要依赖于手术切除。这些程序是侵入性的， 显著的医疗保健成本，并且通常是预防转移进展的不足手段， 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，我们发现增加的核转运蛋白 输出蛋白（XPO）1驱动支架和信号蛋白14-3-3 β的异常定位， SCC细胞中的促生存途径。14-3-3 β基因的遗传缺失抑制了肿瘤的发展， 75%，并阻止恶性进展，而非致瘤性皮肤细胞不受缺乏14-3- 3英里。因此，我们的假设是，抑制两个驱动异常促生存信号的关键调节因子， 将提供一种新的和有效的手段来防止皮肤肿瘤生长和恶性进展， 对周围正常皮肤的毒性。在拟议的研究中，我们将描述机制， XPO 1驱动的异常14-3-3 β信号传导对恶性角质形成细胞的影响（目的1），改善了 我们开发的候选药物可以破坏14-3-3 β促生存信号传导（Aim 2），并提供证据， 14-3-3 β 1和XPO 1抑制剂预防皮肤肿瘤发展有效性的主要证据 以及使用人患者衍生的（PDX）和UV辐射诱导的皮肤癌模型的进展。 这项工作的成功完成预计将导致新的预防和治疗方法， 皮肤癌

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.