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，因为它们的总发病率高于所有人 其他癌症加在一起。因此，这些皮肤癌虽然通常不是致命的，但在治疗中会产生非常高的成本 他们的管理，例如，90%的乳腺癌治疗费用。目前的护理标准是外科手术。 宽边距的切除。主要的发病原因是纤维化、疤痕形成和功能丧失。 治疗。使用5-氨基戊二酸(ALA)的光动力疗法(PDT)代表了一种非毁容的 手术以外的选择，特别是对于多发性肿瘤患者和微小部位的肿瘤。目前， ALA-PDT的疗效不足以与美国的手术实际竞争。 联合光动力生物治疗(CPBT)的项目主题，在项目1，我们的总体 假设肿瘤分化药物可以用来提高ALA-PDT的疗效，从而使PDT 成为NMSC手术的一个可行的替代方案。我们将建立在我们发现的基础上，两个小的 分子，甲氨蝶呤(MTX)和维生素D(维生素D)，可以促进肿瘤细胞分化，同时 时间增加了细胞内光敏剂(PplX)的水平，从而增强了对治疗的反应性。 该项目是翻译性的，包括临床和基础科学部分。AIM 1是临床前研究，而且 使用小鼠鳞状细胞癌和基底细胞癌模型来确定全身分化的最佳给药方案 探员。目标2和目标3是确定外用维生素D和口服MTXas疗效的临床研究 ALA-PDT联合用药。这些目标还将测试新的活体多模式地下成像 PplX检测装置和体外评价C/EBP转录因子作为肿瘤预后标志物的研究 回应。目标4由机械性实验组成，它将检查调节功能和 使用临床前模型和检验，C/EBPS在PplX积聚方面的预后价值 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。这个项目涉及到大量的 与计划的项目4、核心B和核心C进行协作。总而言之，潜在的好处是 公共卫生将为皮肤癌的PDT开发新的合理组合方法 包括操纵肿瘤细胞生理学以增加内源性PplX水平。这将会结合在一起 基于先进的PplX剂量测量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.