Phase I/II study of topical agents for chemoprevention

描述（由申请人提供）：项目IV的总体目标是根除光化性角化病（AK）和发育不良痣（DN），降低非黑色素瘤皮肤癌（NMSC）和黑色素瘤的发病率，并开发基础科学和临床研究方法，作为各种人类上皮癌的化学预防模型。在亚利桑那州东南部，NMSC和黑素瘤的发病率增加了3-7倍。大约60%的鳞状细胞癌（SCC）来自预先存在的AK和/或连续的皮肤表面。AK也可能是黑色素瘤的一个重要风险因素。流行病学研究发现，DN是黑色素瘤的一个强有力的危险因素。研究人员一致认为，通过靶向更早而不是更晚的致癌时间点，成功改变任何癌症自然史的可能性都会增加。我们的研究小组试图剖析导致NMSC和黑色素瘤的UVB和UVA信号转导途径，目的是确定化学预防剂开发的分子靶点，最终将导致更有效的一级和二级预防策略。这种研究方法的一个重要组成部分是需要验证在UVB中识别的分子靶标， 项目I、II和III中UVA诱导的NMSC和黑色素瘤小鼠致癌模型也是 在项目IV的第一年，我们将进行一项临床研究，以交叉验证UVB和UVA皮肤致癌作用的小鼠和人类模型之间的化学预防剂开发的分子靶点。作为该临床研究项目的持续中心焦点，在第1-5年，患有临床前AK、AK、良性痣和DN的参与者将被招募用于局部药物的I期、IIa期和IIb期随机安慰剂对照的癌症预防临床试验（和IIb期试验中的口服维生素A）作为单独药物或组合方案（取决于它们在临床前研究中的活性和/或耐受性，包括：1）紫苏醇，2）阿朴明，3）p38 MAP激酶抑制剂（SB 202190的前药），4）PI-3激酶抑制剂5）EGFR酪氨酸激酶（TK）抑制剂[PD 153035，AG 1478，ZD 1839（Iressa）]，6）紫苏醇前药，7）JNK抑制剂（SP 600125），和8）DFMO前药。所选药物必须显示：1）在至少一种小鼠UV致癌模型或一种转基因小鼠黑素瘤模型中具有活性; 2）在鼠模型中局部和全身无毒; 3）能够NCI-E 25 2 P01 CA 027502 - 23 A1 ALBERTS，D渗透并集中在SKH-1小鼠的全层皮肤中。一个专门的药物开发核心（核心D）将提供最佳的药物或前药配方和药物浓度的每一个局部化学预防剂的I期临床研究。我们还建议表征和量化临床前AK和DN中响应IIa期和IIb期治疗方案而发生的组织病理学、核型和免疫组织化学生物标志物（例如，通过形态学和半胱天冬酶3、PCNA、p53、考克斯-2、c-Fos、CREB-P和项目I-III中鉴定的其他发育分子靶标的凋亡）。最后，我们将确定光学相干断层扫描（OCT）的预测准确性与识别异常的组织病理学和核测定区域的前臂皮肤表皮在研究参与者与太阳受损的皮肤和/或AK。

DESCRIPTION (provided by applicant): The overall goal of Project IV is to eradicate actinic keratosis (AK) and dysplastic nevi (DN), reduce the incidence of non-melanoma skin cancers (NMSC) and melanoma, and to develop basic science and clinical research approaches that will serve as models for the chemoprevention of a wide range of human epithelial cancers. There is a 3-7 fold increased incidence of NMSC and melanoma in southeastern Arizona. Approximately 60% of squamous cell carcinomas (SCC) arise from pre-existing AKs and/or contiguous skin surfaces. AKs may represent a significant risk factor for melanoma as well. Epidemiologic studies found that DN are a strong risk factor for melanoma. Researchers agree that the probability of successfully altering the natural history of any cancer increases by targeting an earlier, rather than a later, time point in carcinogenesis. Our research group has attempted to dissect the UVB and UVA signal transduction pathways leading to NMSC and melanoma with the aim of identifying molecular targets for chemopreventive agent development that ultimately will lead to more effective primary and secondary prevention strategies. An essential part of this research approach is a requirement to validate that the molecular targets identified in the UVB- and UVA-induced NMSC and melanoma mouse carcinogenesis models in Projects I, II and Ill are also present in UVB- and UVA-induced human skin tumor progression, in year 1 of Project IV, we will perform a clinical study to cross validate the molecular targets for chemoprevention agent development between mouse and human models of UVB and UVA skin carcinogenesis. As the continuing central focus of this clinical research project, in years 1-5 participants with preclinical AKs, AKs, benign nevi and DN will be recruited for phase I, lla and lib randomized placebo-controlled cancer prevention clinical trials of topical agents (and oral Vitamin A in phase lib trials) as individual drugs or in combination regimens (depending on their activity and/or tolerance in preclinical studies, including: 1) perillyl alcohol, 2) apomine, 3) p38 MAP kinase inhibitor (prodrug of SB202190), 4) PI-3 kinase inhibitor (LY294002 or inositol hexaphosphate), 5) EGFR tyrosine kinase (TK) inhibitors [PD153035, AG1478, ZD1839 (lressa)], 6) perillyl alcohol prodrug, 7) JNK inhibitor (SP600125), and 8) DFMO prodrug. Agents selected must be shown to be: 1) active in at least one mouse UV carcinogenesis model or one transgenic mouse melanoma model; 2) locally and systemically nontoxic in murine models; and 3) able NCI-E 25 2 P01 CA027502-23A1 ALBERTS, D to penetrate and concentrate in full thickness skin from SKH-1 mice. A specialized Drug Development Core (Core D) will supply the most optimal drug or prodrug formulations and drug concentrations for each topical chemopreventive agent for Phase I clinical studies. We also propose to characterize and quantify histopathologic, karyometric, and immunohistochemical biomarkers (e.g. apoptosis by morphology and caspase 3, PCNA, p53, COX-2, c-Fos, CREB-P and other developmental molecular targets identified in Projects I-Ill) that occur in preclinical AKs and DN in response to phase Ila and lib treatment regimens. Finally, we will determine the predictive accuracy of optical coherence tomography (OCT) with respect to identification of abnormal histopathologic and karyometric areas of forearm skin epidermis in study participants with sun damaged skin and/or AKs.