Small Molecule Enhancers of Photodynamic Therapy for Skin Cancer

非黑色素瘤皮肤癌（NMSC），包括鳞状细胞癌（SCC）和基底细胞癌（BCC）， 对卫生保健系统有重大影响，因为其总体发病率高于所有 其他癌症合并。因此，虽然通常不是致命的，但这些皮肤癌导致非常高的治疗成本。 他们的管理，例如，治疗乳腺癌的90%的费用。目前的标准治疗是外科手术 宽边缘切除。主要的发病率源于纤维化、瘢痕形成和术后功能丧失。 治疗使用5-氨基特维酸（ALA）的光动力疗法（PDT）代表了一种非毁容疗法， 这是手术的替代方案，尤其适用于多发肿瘤患者和脆弱部位的肿瘤。目前， ALA-PDT的疗效不足以与美国的外科手术竞争。 联合光动力生物治疗（CPBT）的计划主题，在项目1中，我们的总体 假设肿瘤分化剂可用于改善ALA-PDT的功效， 成为NMSC手术的可行替代方案。我们将建立在我们发现的两个小的 分子甲氨蝶呤（MTX）和维生素D（Vit D）可以增加肿瘤细胞的分化，同时 时间增加细胞内光敏剂（PpIX）的水平，从而增强对治疗的响应性。 该项目具有转化性质，包括临床和基础科学部分。目标1是临床前， 使用SCC和BCC的小鼠模型来确定系统分化的最佳给药方案， 剂目的2和3是确定局部维生素D和口服MTX的疗效的临床研究 与ALA-PDT的组合药剂。这些目标还将测试新的体内多模态次表面成像 用于PpIX检测的装置，并评估C/EBP转录因子作为肿瘤预后标志物的离体 反应目的4包括机械实验，将检查调节功能和 C/EBP在PplX积累方面的预后价值，使用临床前模型并检查 来自临床研究的组织库皮肤肿瘤标本。目标4很重要，因为 实验将有助于进一步改进治疗设计。该项目涉及重大 与项目4、核心B和核心C的合作。总之， 公共卫生将是皮肤癌PDT的新的合理组合方法的发展， 包括操纵肿瘤细胞生理学以增加PpIX的内源水平。这将与 基于先进的PplX剂量测定和测量的个性化治疗计划， 分化反应分子标记，以优化治疗反应。

Non-melanoma skin cancers (NMSC), comprising squamous cell (SCC) and basal cell carcinomas (BCC), have a significant impact upon the health care system because their overall incidence is higher than for all other cancers combined. Therefore, while not usually fatal, these skin carcinomas incur a very high cost for their management, e.g., 90% of the cost of treating breast cancer. The current standard of care is surgical excision with wide margins. Major morbidity stems from fibrosis, scarring, and loss of function after treatment. Photodynamic therapy (PDT) using 5-aminotevulinicacid (ALA) represents a non-disfiguring alternative to surgery, especially for patients with multiple tumors and for tumors in delicate sites. Currently, the efficacy of ALA-PDT is not adequate to realistically compete with surgery in the U.S.A. Based on one of the Program themes of Combination Photodynamic Biologic Therapy (CPBT), in Project 1, our overall hypothesis is that tumor-differentiating agents can be used to improve the efficacy of ALA-PDT so that PDT becomes a viable alternative to surgery for NMSC. Wewill build upon our discovery that two small molecules, methotrexate (MTX) and vitamin D (Vit D), can increase tumor cell differentiation and at the same time increase the levels of photosensitizer (PplX) within the cells, thus enhancing responsiveness to therapy. The project is translational in nature, with clinical and basic science components. Aim 1 is preclinical, and uses mouse models of SCC and BCC to determine optimal dosing regimens for the systemic differentiating agent. Aims 2 and 3 are clinical studies to determine the efficacy of topical Vit D and oral MTXas combination agents with ALA-PDT. These Aims will also test new in vivo multimodal subsurface imaging devices for PplX detection, and evaluate C/EBP transcription factors ex vivo as prognostic markers of tumor response. Aim 4 consists of mechanistic experiments that will examine regulatory functions and the prognostic value of the C/EBPs in terms of PplX accumulation, using the preclinical models and examining tissue-banked skin tumor specimens from the clinical studies. Aim 4 is significant because those experiments will contribute to further improvements in the treatment design. The project involves significant collaborations with Project 4, Core B, and Core C of the Program. In summary, the potentialbenefits to public health will be the development of new rational combination approaches for PDT of skin cancer that include the manipulation of tumor cell physiology to increase endogenous levels of PplX. This will be coupled with individualized treatment planning based upon advanced PplX dosimetry and measurement of differentiation-responsive molecular markers, to optimize treatment response.