Targeting aberrant anti-apoptotic signaling for prevention of skin cancer

摘要 包括鳞状细胞癌在内的非黑色素瘤皮肤癌是最常见的癌症 在美国确诊的S，绝大多数病例是由紫外线(UV)引起的 辐射。鳞状细胞癌通常由癌前病变发展而来，为干预提供了机会 防止恶性疾病和转移进展。临床可发现的恶性病变的治疗和 前驱光化性角化病仍在很大程度上依赖于手术切除。这些手术是侵入性的，携带着 巨大的医疗费用，而且往往不足以防止肿瘤的转移进展 免疫功能受损的病人。因此，需要更有效的基于机制的治疗方法。 没有副作用或副作用很小。在初步调查中，我们发现增加了核转运体 Exportin(Xpo)1驱动支架和信号蛋白14-3-3的异常定位以激活 鳞状细胞癌细胞中的生存途径。14-3-3基因缺失通过抑制肿瘤的发展 75%，并阻止恶性进展，而非致瘤皮肤细胞不受14-3- 3个。因此，我们的假设是，抑制驱动异常生存信号的两个关键调控因子 将提供一种新的有效手段，以最少的费用防止皮肤肿瘤的生长和恶性进展 对周围正常皮肤有毒性。在拟议的研究中，我们将描述这些机制和 XPO1驱动的异常14-3-3信号对恶性角质形成细胞的影响(目标1)，改进 我们开发的候选药物可以干扰14-3-3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有效性的主要证据 使用人类患者来源(PDX)和紫外线照射诱导的皮肤癌模型进行研究和进展。 这项工作的成功完成有望带来预防和治疗的新方法 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.