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.

非黑色素瘤皮肤癌（NMSC），即皮肤基底细胞癌（BCC）和 鳞状细胞癌（SCC）是器官移植中最常见的恶性肿瘤 收件人（OTR）。 OTR的皮肤SCC风险更高，增加了10倍 BCC的风险比一般人群的风险，当他们发生时，NMSC的行为会更多 积极地。例如，OTR中的SCC转移速率为7％，远高于 普通人群。当前预防NMSC的方法主要由太阳和 避免晒黑床和定期使用防晒霜。这些措施已被证明是 不足。口服类维生素类似于OTR中有效的化学预防剂，但以剂量为单位 必需的耐受性不佳。 UAB30是一种新型的RXR选择性类维生素类似（即rexinoid），这是一个 动物模型中SCC和其他上皮肿瘤的有效化学预防剂，并且具有 在正常个体中，在I期人类临床试验中显示出良好的耐受性。我们计划 在OTRS中进行口服UAB30的随机，双盲，安慰剂对照的生物标志物研究 具有精良损害以及BCC和/或SCC的历史。这项短期临床试验的目的 是确定UAB30是否对与该分子相关的分子有保护作用 OTR中NMSC的开发。我们计划确定是否有更多的OTR 随机接收口服UAB30的皮肤生物标志物将降低30％ NMSC的开发。细胞增殖的标记Cyclin D1将是主要终点。 要评估的其他生物标志物包括与增殖和相关的其他分子 凋亡，在DNA损伤修复和SRC途径中关闭目标分子，全反替诺 酸基因和与宿主抗肿瘤免疫反应相关的参数。我们也计划 调查前启示性阳性性角膜结构是否会进行回归以及是否发作 在OTR中将抑制新的活化性角化作用，而非OTR参与者则将其随机分为UAB30。 最后，我们将评估OTR中口服UAB30的安全性。这是确定的合理第一步 在较大的OTR中，将UAB30作为NMSC的化学预防剂的可行性 长期，更昂贵的临床试验。它还可以确定筛选未来的程序 在人类体内化学预防作用的rexinoids。