Topical Chemoprevention of Skin Cancer Biomarkers

 描述（由申请人提供）：非黑色素瘤皮肤癌（NMSC;皮肤基底细胞癌和鳞状细胞癌）是美国人类最常见的恶性肿瘤。它们是相当多的发病率的来源，是卫生保健系统的巨大成本。目前的预防方法主要包括避免阳光和晒黑床以及定期使用防晒霜。不幸的是，这些措施已被证明是不够的，与大多数其他恶性肿瘤相比，NMSC的发病率继续增加。显示出预防非黑色素瘤皮肤癌的前景的两种药剂是抑制环氧合酶的非甾体抗炎药（NSAID）和二氟甲基鸟氨酸（DFMO），其是酶鸟氨酸脱羧酶的非竞争性抑制剂。在其他器官系统中，这些药剂具有协同癌症化学预防活性。由于皮肤易于接触，因此可以将这些药物的局部制剂用于皮肤癌的化学预防，而不会遇到全身毒性的可能性。我们假设，局部应用考克斯抑制剂双氯芬酸和/或局部DFMO 9个月是一种安全有效的方法，可逆转有发生非黑色素瘤皮肤癌风险的受试者发生非黑色素瘤皮肤癌相关的生物标志物，并可预防新发光化性角化病的发生。测试 根据我们的假设，我们计划对100名有基底细胞和/或鳞状细胞皮肤癌和至少8种光化性角化病病史的受试者进行随机、双盲、安慰剂对照试验。患者将随机接受：局部DFMO +安慰剂;安慰剂+局部双氯芬酸;局部DFMO +局部双氯芬酸;安慰剂+安慰剂。我们将评估局部DFMO +局部双氯芬酸是否改变皮肤生物标志物，重点关注前列腺素E2、多胺和鸟氨酸脱羧酶、增殖和凋亡标志物（Ki 67、PCNA、细胞周期蛋白D1、半胱天冬酶3、tunel测定、Bcl-2、Bax）以及Akt/ERK 1/2轴中的分子。计划进行研究，以确定局部DFMO和/或局部双氯芬酸治疗是否耐受良好，且无显著毒性体征。我们还将评估随机分配至局部双氯芬酸和/或局部DFMO组的受试者在9个月内新发光化性角化病的发生率是否低于安慰剂组。这些研究的最终目标是确定是否应在预防非黑色素瘤皮肤癌的临床试验中评价局部双氯芬酸和/或DFMO。

 DESCRIPTION (provided by applicant): Non-melanoma skin cancers (NMSCs; cutaneous basal cell carcinomas and squamous cell carcinomas) are the most common malignancies in humans in the United States. They are the source of considerable morbidity and are a tremendous cost to the health care system. Current methods for their prevention have consisted primarily of sun and tanning bed avoidance and the regular use of sunscreens. Unfortunately, these measures have proven inadequate, and in contrast to most other malignancies, the incidence of NMSCs continues to increase. Two agents that show promise for the prevention of non-melanoma skin cancers are non-steroidal anti-inflammatory agents (NSAIDs), which inhibit the cyclooxygenase enzyme, and difluoromethylornithine (DFMO), a non-competitive inhibitor of the enzyme ornithine decarboxylase. In other organ systems, these agents have synergistic cancer chemopreventive activities. Because the skin is readily accessible, it may be possible to apply topical formulations of these agents for the chemoprevention of skin cancers without encountering the potential for systemic toxicity. We hypothesize that topical application of the COX inhibitor diclofenac and/or topical DFMO for 9 months is a safe and effective method of reversing biomarkers associated with the development of non-melanoma skin cancers in subjects at risk for their development and will prevent the onset of new actinic keratoses. To test our hypothesis, we plan to conduct a randomized, double-blind, placebo-controlled trial of 100 subjects with a history of basal cell and/or squamous cell skin cancer and at least 8 actinic keratoses. Patients will be randomized to receive: topical DFMO + placebo; placebo + topical diclofenac; topical DFMO + topical diclofenac; placebo + placebo. We will assess whether topical DFMO + topical diclofenac alters skin biomarkers focusing on prostaglandin E2, polyamines and ornithine decarboxylase, proliferation and apoptosis markers (Ki67, PCNA, cyclin D1, caspase 3, tunel assay, Bcl-2, Bax), and molecules in the Akt/ERK1/2 axis. Studies are planned to determine if treatment with topical DFMO and/or topical diclofenac is well-tolerated without signs of significant toxicity. We will also assess whether subjects randomized to topical diclofenac and/or topical DFMO develop over a 9 month period of time fewer new actinic keratoses than those who are placed on placebo. The ultimate goal of these studies will be to determine whether topical diclofenac and/or DFMO should be evaluated in a clinical trial for the prevention of non-melanoma skin cancers.