Project 1: Small Molecule Enhancers of Photodynamic Therapy for Skin Cancer

项目1摘要 项目1将开发用于非黑色素瘤皮肤癌（NMSC）的联合光动力疗法（cPDT）， 包括鳞状细胞癌（SCC）和基底细胞癌（BCC）。NMSC目前接受以下治疗： 手术切除，但需要更好的替代方案，特别是对于器官移植患者谁发展 频繁和积极的SCC，并为基底细胞痣综合征患者谁发展数百BCC。 以前，我们发现用分化剂（甲氨蝶呤，维生素D）进行生化操作， [Vit D]和5-氟尿嘧啶[5-FU]）增强血红素途径活性和原卟啉IX（PpIX）积累。 这些发现现在将转化为临床疗效的改善。AIM 1将检查SCC的cPDT（ 最致命的NMSC）。这是一项临床试验， 联合治疗提高了侵袭性NMSC高风险患者（器官转移患者）原位SCC的疗效 移植或高度光损伤的皮肤）。将保存皮肤活检和血液用于目标3。AIM 2将 研究cPDT治疗BCC（所有癌症中最普遍的癌症）。PDT受到非均匀 光敏剂（PpIX）在肿瘤中的分布，但维生素D预处理诱导更均匀的分布。 BCC患者将先用5-FU、维生素D或安慰剂预处理，然后用ALA治疗4小时。 用于评估PpIX分布;然后用红光治疗肿瘤。肿瘤的组织学清除率 3个月将通过手术切除确认。AIM 3将研究新的cPDT方法和新的检测方法 来帮助患者进行个性化治疗。来自项目3的脂质体靶向纳米构建体将用于 在临床前递送针对EGFR或VEGF/c-Met的小分子抑制剂（沿着光敏剂BPD） BCC皮肤癌模型，包括来自Ptch 1 +/-小鼠的BCC皮肤外植体模型。的预测价值 无创监测患者皮肤中的PpIX（使用项目4中开发的光学工具）， p53水平和胸苷合酶基因等位基因，将通过与病变清除率的相关性进行检测。 临床研究。临床前研究将提高对机制的理解，并建议未来 个体化治疗和最大化cPDT治疗反应的方法。

PROJECT 1 ABSTRACT Project 1 will develop combination photodynamic therapy (cPDT) for non-melanoma skin cancers (NMSC), including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). NMSC are currently treated by surgical excision, but better alternatives are needed, especially for organ transplant patients who develop frequent and aggressive SCC, and for Basal Cell Nevus Syndrome patients who develop hundreds of BCCs. Previously, we discovered that biochemical manipulation with differentiating agents (methotrexate, vitamin D [Vit D], and 5-fluorouracil [5-FU]) enhances heme pathway activity and protoporphyrin IX (PpIX) accumulation. Those findings will now be translated into improved efficacy in the clinic. AIM 1 will examine cPDT for SCC (the most lethal NMSC) using topical 5-FU prior to ALA and blue light. This is a clinical trial to test whether the combination improves efficacy for SCC in-situ in patients at high risk for aggressive NMSC (patients with organ transplants, or highly photodamaged skin). Skin biopsies and blood will be saved for use in Aim 3. AIM 2 will investigate cPDT for BCC (the most prevalent of all cancers). PDT is hampered by a nonhomogeneous photosensitizer (PpIX) distribution in tumors, but Vit D pretreatment induces a more homogenous distribution. Patients with BCC will be pretreated with 5-FU, Vit D, or placebo followed by ALA for 4 hr. A skin biopsy will be taken to assess PpIX distribution; tumors will then be treated with red light. Histological clearance of tumors at 3 months will be confirmed by surgical excision. AIM 3 will investigate new cPDT approaches and new assays to help individualized patient treatments. Liposomal targeting nanoconstructs from Project 3 will be used to deliver small molecule inhibitors against EGFR or VEGF/c-Met (along with photosensitizer BPD) in preclinical models of BCC skin cancer, including a BCC skin explant model from Ptch1 +/- mice. The predictive value of noninvasive monitoring of PpIX in patient skin (using optical tools developed in Project 4), and of measuring p53 levels and thymidine synthase gene alleles, will be tested by correlation with lesion clearance rates in the clinical studies. The preclinical studies will improve understanding of mechanisms and suggest future approaches to individualize the treatments and maximize therapeutic responses to cPDT.