Project 1: Evaluation of UAB30 on skin cancer biomarkers in human renal transplant recipients

非黑色素瘤皮肤癌（NMSC），即皮肤基底细胞癌（BCC）和 鳞状细胞癌是器官移植中最常见的恶性肿瘤 收件人（OTR）。OTR的皮肤SCC风险高65- 250倍， BCCs的风险比一般人群高，当它们发生时，NMSC表现得更 咄咄逼人例如，OTR中SCC转移率为7%，远高于 普通民众。目前用于预防NMSC的方法主要包括阳光和 避免日光浴床和经常使用防晒霜。事实证明，这些措施 不足口服类维生素A是OTR的有效化学预防剂，但剂量 需要，耐受性差。UAB 30是一种新的RXR选择性类维生素A（即rexinoid）， 有效的化学预防剂，用于SCC和其他上皮肿瘤的动物模型， 在正常个体的I期人体临床试验中显示出良好的耐受性。我们计划 在OTR中进行一项口服UAB 30的随机、双盲、安慰剂对照生物标志物研究 有光化性损伤和基底细胞癌和/或鳞状细胞癌病史这项短期临床试验的目的是 是为了确定UAB 30是否对与细胞凋亡相关的分子具有保护作用。 在OTR中开发NMSC。我们计划确定是否有更大比例的OTR 随机接受口服UAB 30的患者将具有与以下相关的皮肤生物标志物的>30%的减少： NMSC的发展。细胞周期蛋白D1（细胞增殖的标志物）将是主要终点。 待评估的其他生物标志物包括与增殖相关的其他分子， 细胞凋亡，DNA损伤修复和Src通路中的脱靶分子，全反式维甲酸 酸基因和与宿主抗肿瘤免疫应答相关的参数。我们还计划 研究癌前光化性角化病是否会消退， 新的光化性角化病将在OTR和非OTR参与者中被抑制，这些参与者被随机分配到UAB组30。 最后，我们将评估口服UAB 30在OTR中的安全性。这是理性的第一步 在更大的， 长期的，更昂贵的临床试验。它还可以确定未来筛查的程序 rexinoids在人体内的化学预防作用。

Non-melanoma skin cancers (NMSCs) i.e. cutaneous basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) are the most common malignancies in organ transplant recipients (OTRs). OTRs have a 65-250x greater risk of cutaneous SCCs and a 10x increased risk of BCCs than the general population, and when they do occur, NMSCs behave more aggressively. For example, the rate of SCC metastases in OTRs is 7%, which is much higher than the general population. Current methods for prevention of NMSCs consist primarily of sun and tanning bed avoidance and the regular use of sunscreens. These measures have proven to be inadequate. Oral retinoids are effective chemopreventive agents in OTRs, but at the doses required, are poorly tolerated. UAB30 is a novel RXR selective retinoid (i.e. rexinoid), which is a potent chemopreventive agent for SCCs and other epithelial tumors in animal models, and has been shown to be well-tolerated in phase I human clinical trials in normal individuals. We plan to conduct a randomized, double-blind, placebo-controlled biomarker study of oral UAB30 in OTRs with actinic damage and a history of BCC and/or SCC. The purpose of this short-term clinical trial is to determine whether UAB30 has a protective effect on molecules associated with the development of NMSC in OTRs. We plan to determine whether a greater percentage of OTRs randomized to receive oral UAB30 will have >30% reduction in skin biomarkers associated with development of NMSC. Cyclin D1, a marker of cell proliferation, will be the primary endpoint. Other biomarkers to be evaluated include additional molecules associated with proliferation and apoptosis, off target molecules in the DNA damage repair and Src pathways, all-trans-retinoic acid genes, and parameters associated with the host anti-tumor immune response. We also plan to investigate whether premalignant actinic keratoses will undergo regression and if the onset of new actinic keratoses will be inhibited in OTR and non-OTR participants randomized to UAB30. Finally, we will evaluate the safety of oral UAB30 in OTRs. This is a rational first step to determine the feasibility of testing UAB30 as a chemopreventive agent for NMSC in OTRs prior to a larger, long-term, and more costly clinical trial. It may also identify procedures for screening future rexinoids for their chemopreventive actions in vivo in humans.