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

项目1：UAB30对人肾移植受者皮肤癌生物标志物的评价

• 批准号: 10263921
• 负责人: Craig A Elmets
• 金额: $ 21.53万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263921
• 关键词: Acute Lymphocytic Leukemia; Affect; Alabama; Animal Model; Apoptosis; Basal Cell; Basal cell carcinoma; Binding; Biological Markers; Cancer Etiology; Cell Culture Techniques; Cell Proliferation; Cells; Chemoprevention; Chemopreventive Agent; Clinical; Clinical Trials; Cutaneous; Cutaneous T-cell lymphoma; Cyclin D1; DNA Damage; DNA Repair; Development; Dose; Double-Blind Method; Economic Burden; Epithelial; Evaluation; Future; General Population; Genes; Healthcare Systems; Human; Hypertriglyceridemia; Immune response; Immunocompromised Host; Incidence; Individual; Kidney Transplantation; Liver X Receptor; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Medicine; Methods; Mus; Neoplasm Metastasis; Neoplastic Keratinocyte; Neuroblastoma; Oral; Oral Administration; Organ Transplantation; Participant; Pathway interactions; Patient risk; Pharmaceutical Preparations; Phase; Placebos; Prevention; Process; Production; RXR; Randomized; Recommendation; Recording of previous events; Retinoids; Risk; Safety; Screening procedure; Serum; Signal Pathway; Skin; Skin Cancer; Skin Carcinoma; Skin Neoplasms; Squamous cell carcinoma; Structure; Sun Exposure; Sunscreening Agents; Testing; The Sun; Toxic effect; Transplant Recipients; Tretinoin; Triglycerides; Tumor-infiltrating immune cells; Ultraviolet Rays; Universities; Up-Regulation; Vitamin A; alitretinoin; analog; anti-tumor immune response; arm; cancer biomarkers; cancer chemoprevention; cancer prevention; chemotherapy; cost; cytokine; design; feasibility testing; in vivo; inhibitor/antagonist; interest; keratinocyte; kidney allograft; malignant breast neoplasm; next generation; novel; photoprotection; premalignant; prevent; primary endpoint; protective effect; response; screening; skin cancer prevention; skin squamous cell carcinoma; tanning booths; treatment duration; tumor; vitamin analog

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.

非黑素瘤皮肤癌(NMSCs)，即皮肤基底细胞癌(BCC)和 摘要鳞状细胞癌是器官移植中最常见的恶性肿瘤。 收件人(OTR)。OTRS患皮肤鳞状细胞癌的风险是65-250倍，是10倍 BCC的风险高于一般人群，当它们确实发生时，NMSCs的行为更多 咄咄逼人。例如，OTRS的鳞状细胞癌转移率为7%，远远高于 普通民众。目前预防NMSCs的方法主要包括SUN和 避免在日光浴床上晒太阳，经常使用防晒霜。这些措施已被证明是 不够充分。口服维甲酸是OTRs有效的化学预防药物，但剂量 是必需的，是不能容忍的。UAB30是一种新的RXR选择性维甲酸(即rexinid)，是一种 对动物模型中的鳞状细胞和其他上皮性肿瘤有效的化学预防药物，并已 在正常人的I期人体临床试验中被证明耐受性良好。我们计划 在OTRs中进行口服UAB30的随机、双盲、安慰剂对照生物标志物研究 有光化性损害和BCC和/或SCC病史。这项短期临床试验的目的 是为了确定UAB30是否对与 OTRS中NMSC的发展。我们计划确定是否有更大比例的OTRs 随机接受口服UAB30将使与以下疾病相关的皮肤生物标志物减少30% NMSC的发展。细胞增殖的标志物--细胞周期蛋白D1将成为主要终点。 其他需要评估的生物标记物包括与增殖和 细胞凋亡，脱靶分子在DNA损伤修复和Src通路，全反式维甲酸 酸性基因，以及与宿主抗肿瘤免疫反应相关的参数。我们还计划 目的：研究癌前光化性角化病是否会消退，以及 新的光化性角化病将在OTR和非OTR参与者中被抑制，随机分为UAB30组。 最后，我们将评估口服UAB30在OTRS中的安全性。这是理性的第一步，要确定 在OTRS中检测UAB30作为NMSC化学预防药物的可行性， 长期的、成本更高的临床试验。它还可能确定未来筛查的程序 Rexinoid在人体内的化学预防作用。