Combination Therapy With 5-FU and PDT For The Treatment Of Post-Transplant Premal

描述(申请人提供)：器官移植患者，一个免疫抑制的人群，是发展为鳞状细胞癌(SCC)的高风险人群，这种癌症是由称为光化性角化病(AK)的表皮发育不良的癌前区域引起的。AK的早期治疗是防止进展为侵袭性鳞癌的关键，但目前的治疗方法大多无效，因此侵袭性和转移性鳞癌在这些患者中经常发生。光动力疗法(PDT)是一种结合局部前药，氨基酮丙酸(ALA)或其甲酯(MALA)被肿瘤细胞选择性摄取并代谢转化为原卟啉IX(PpIX)的方法。PPIX是一种吸收可见光的光敏剂；对含有高PPIX水平的癌前细胞进行照射会导致选择性细胞杀伤。PDT是一种有吸引力的治疗方式，因为它治疗的表面积很大，是非侵入性的，现在被认为优于大多数其他标准的治疗AK的方法，包括外用5-氟尿嘧啶(5FU)乳膏。然而，在移植患者中，即使是PDT也不能令人满意，治疗后一年AK的复发率为20%-40%。目前的建议将验证这样一种假设，即PDT与局部短期(6天)的5-FU预处理方案相结合可以改善PDT的疗效。我们的临床前动物研究表明，短接触的5-FU方案可以刺激小鼠皮肤肿瘤中PPIX水平增加3倍。我们建议验证这一假设，即5-FU/PDT联合治疗将提高人类AK皮损中PpIX的水平，并可能被证明比单独使用PDT更有效地治疗和预防AK。这项试点研究将招收40名受试者。一组20人将是实体器官移植接受者(肾或肝移植后状态)，面部或头皮有4个或更多AK病变。第二组将由20名正常对照组(有4个或更多AK的非移植个体)组成，接受类似的治疗，以控制免疫抑制的效果。在这项探索性研究中，将检查PpIX水平(主要终点)的生化变化以及从病变消退、病变复发以及皮肤和血液中生物标记物的变化(次要终点)方面的临床有效性指标。患者将被随机分成一侧接受局部5-FU预处理(每天6天)，另一侧不接受预处理。在第7天，将使用荧光监测来测量皮损中的PpIX水平：(I)在使用Mala之前；(Ii)在使用Mala之后3小时；以及(Iii)在暴露于治疗性光(37J/cm2红光)之后立即。在PDT后每3个月对患者进行为期1年的随访，以确定AK清除和AK发生率。总之，AIM 1将测试5-FU预处理是否可以选择性地增加AK皮损内产生的光敏剂(PpIX)。目的2测试5-FU/PDT联合方案的临床安全性和有效性，以及预测生物标记物的有效性。这项研究将通过建立一种治疗方案的原则证据，从而为公众健康提供潜在的好处，该疗法可能大大推迟器官移植受者皮肤癌的发病，而器官移植受者是目前尚无有效选择的高危人群。

DESCRIPTION (provided by applicant): Organ transplant patients, an immunosuppressed population, are at high risk for developing squamous cell carcinoma (SCC) that arise from preneoplastic areas of epidermal dysplasia called actinic keratoses (AK). Early treatment of AK is critical to prevent progression to invasive SCC, but current treatments are largely ineffective, so that invasive and metastatic SCC occur frequently in these patients. Photodynamic therapy (PDT) is a modality that combines topical prodrugs, either aminolevulinic acid (ALA) or its methyl ester (mALA), which are selectively taken up by tumor cells and metabolically converted to protoporphyrin IX (PpIX). PpIX is a photosensitizer that absorbs visible light; illumination of preneoplastic cells containing high PpIX levels causes selective cell killing. PDT is an attractive modality because it treats a large surface area, is noninvasive, and is now considered superior to most other standard treatments for AK, including topical 5- fluorouracil cream (5FU). Yet in transplant patients, even PDT remains unsatisfactory, with recurrence rates for AK of 20-40% at 1 year post-therapy. The current proposal will test the hypothesis that PDT efficacy can be improved by combining PDT with a short (6-day) pretreatment regimen of topical 5-FU. Our preclinical animal studies showed that a short-contact 5-FU regimen can stimulate a 3-fold increase in PpIX levels in skin tumors in mice. We propose to test the hypothesis that 5-FU/PDT combination therapy will enhance PpIX levels in AK lesions in humans, and may prove more effective for treatment and prevention of AK, than PDT alone. This pilot study will enroll 40 subjects. One group of 20 subjects will be solid organ transplant recipients (status-post kidney or liver transplantation) with 4 or more AK lesions on the face or scalp. The second group will consist of 20 normal controls (non-transplant individuals with 4 or more AK), similarly treated, to control for effects of immunosuppression. Biochemical changes in PpIX levels (primary endpoint) and indicators of clinical effectiveness in terms of lesion resolution, lesion recurrence, and changes in biomarkers in skin and blood (secondary endpoints) will be examined in this exploratory study. Patients will be randomized to receive topical 5-FU pretreatment (daily for 6 days) on one side, and no pretreatment on the contralateral side. On day 7, levels of PpIX in lesions will be measured using fluorimetric monitoring: (i) before mALA application; (ii) at 3 hr after mALA application; and (iii) immediately after exposure to therapeutic light (37 J/cm2 of red light). Patients will be followed every 3 months for 1 year after PDT to determine AK clearance and AK incidence. In summary, Aim 1 will test whether 5-FU pretreatment can selectively increase photosensitizer (PpIX) produced within AK lesions. Aim 2 will test the 5-FU/PDT combination regimen in terms of clinical safety and efficacy, and usefulness of predictive biomarkers. This study will provide potential benefits to public health by establishing proof-of-principle for a therapeutic regimen that may substantially delay the onset of skin cancers in organ transplant recipients, a high-risk population for whom no effective option is currently available.