Topical Chemoprevention of Skin Cancer Biomarkers

 描述(申请人提供)：非黑色素瘤皮肤癌(NMSCs；皮肤基底细胞癌和鳞状细胞癌)是美国最常见的人类恶性肿瘤。它们是相当大的发病率的来源，是卫生保健系统的巨大成本。目前预防它们的方法主要包括避免晒太阳和晒黑床，以及定期使用防晒霜。不幸的是，这些措施被证明是不充分的，与大多数其他恶性肿瘤相比，NMSCs的发病率继续上升。两种有望预防非黑色素瘤皮肤癌的药物是非类固醇抗炎药(NSAIDs)和二氟甲基鸟氨酸(DFMO)，NSAIDs抑制环氧合酶，DFMO是鸟氨酸脱羧酶的非竞争性抑制剂。在其他器官系统中，这些药物具有协同的癌症化学预防活性。由于皮肤很容易接触到，因此有可能在不遇到全身毒性的情况下，应用这些药物的局部配方来化学预防皮肤癌。我们推测，局部应用COX抑制剂双氯芬酸和/或局部应用DFMO 9个月是一种安全有效的方法，可以逆转与非黑色素瘤皮肤癌发展相关的生物标志物，并将防止新的光化性角化病的发生。为了测试 根据我们的假设，我们计划对100名有基底细胞和/或鳞状细胞皮肤癌病史和至少8例光化性角化病的受试者进行随机、双盲、安慰剂对照试验。患者将随机接受：外用DFMO+安慰剂；安慰剂+外用双氯芬酸；外用DFMO+外用双氯芬酸；安慰剂+安慰剂。我们将评估外用DFMO+外用双氯芬酸是否会改变皮肤生物标记物，重点是前列腺素E2、多胺和鸟氨酸脱羧酶、增殖和凋亡标记物(Ki67、增殖细胞核抗原、细胞周期蛋白D1、半胱氨酸天冬氨酸氨基转移酶3、TUNEL法、Bcl2、Bax)以及Akt/ERK1/2轴上的分子。计划进行研究以确定外用DFMO和/或外用双氯芬酸的治疗是否耐受性良好，没有明显毒性的迹象。我们还将评估随机服用双氯芬酸和/或外用DFMO的受试者在9个月的时间内是否比服用安慰剂的受试者发生新的光化性角化病更少。这些研究的最终目标将是确定是否应该在预防非黑色素瘤皮肤癌的临床试验中评估外用双氯芬酸和/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.