Vitamin D and Photodynamic Therapy for Human Skin Cancer (SCC and BCC)

项目摘要/摘要 基底细胞癌(BCC)、鳞状细胞癌(SCC)和原位鳞状细胞癌前病变(CIS) 光化性角化病)是所有人类肿瘤中最常见的，并在很大程度上导致 国家医疗负担。虽然现有的技术，如冷冻消融或外科切除，通常 治愈，这些治疗会导致疤痕，尤其是皮肤高危患者的容貌 癌症(即慢性严重光损伤患者；器官移植引起的免疫抑制；或 基底细胞痣综合征(BCNS)。光动力疗法(PDT)结合了光敏剂 (通过注射氨基酮丙酸诱导的原卟啉PpIX)用可见光激活， 而且是一种完全不会留下疤痕的技术。光动力疗法被FDA批准用于广泛的疾病的现场治疗 在欧洲国家，光动力疗法也被批准用于治疗鳞状细胞癌和基底细胞癌。在 然而，美国批准PDT治疗SCC和BCC将需要进一步的临床试验来证明其有效性 类似于现有技术(破坏性消融)。作为一种提高光动力疗法疗效的新方法，我们在 鳞癌和基底细胞癌动物模型在ALA-PDT前短暂给予维生素D(VD)可增强PpIX 蓄积和PDT疗效。口服(饮食)形式的VD(胆钙化醇；D3，每天给药10,000国际单位) 10天)使PDT诱导的肿瘤杀伤率增加数倍，并且非常安全，诱导风险很小 高钙血症。在这项拨款中，我们建议在人体临床试验中测试这种方法，使用口服D3作为一种 光动力疗法的新佐剂。目标1将检查VD状态(血清25OH-D3)与PDT的关系 对独联体的功效。Subaim 1a是一项纵向研究，旨在测试血清25OH-D3水平与 我们临床上常规PDT患者的治疗结果，并检查某些特定的预测价值 生物标记物(如VDR等位基因多态)。Subaim 1b是一项干预试验，旨在评估 在PDT前给予新佐剂D3(暂时性口服D3)。D3/PDT联合治疗的结果(Subaim 1b) 将与仅在D3后(Subaim 1a)的结果进行比较，并按VD缺乏状态分层。在目标2中，我们将 检查新辅助剂D3/PDT在BCNS(Gorlin-Goltz综合征)患者中的潜在益处。这些 患有多发性基底细胞癌的患者将接受3个月一次的PDT治疗，以及肿瘤缩小率 将与血清25OH-D3水平相关。每个患者将作为他/她自己的随机对照 前两次PDT治疗的顺序，一次使用新佐剂D3，另一次不使用新辅助D3。 第三次PDT治疗将在D3将血清VD水平调整到正常水平后进行 补充剂。这种方法将使我们能够确定新辅助剂D3/PDT是否可以帮助所有患者， 即使是VD缺乏的个体，也可以通过定制D3剂量。总而言之，我们期待这群临床 为新的治疗模式奠定基础的试验，即皮肤癌的新佐剂D3/PDT。这个 对公众健康的潜在好处是，数据显示PDT通过这种安全和简单的方法改善了疗效 该方法将为早期鳞状细胞癌和基底细胞癌手术以外的无疤痕替代治疗奠定基础。

PROJECT SUMMARY/ ABSTRACT Basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and squamous precancers in-situ (CIS, also known as actinic keratoses), are the most common of all human neoplasias and contribute significantly to the national healthcare burden. While existing techniques such as cryoablation or surgical excision are generally curative, those treatments cause scarring that can be especially disfiguring in patients at high risk for skin cancer (i.e., patients with chronic severe photodamage; immunosuppression due to organ transplantation; or Basal Cell Nevus Syndrome, BCNS). Photodynamic therapy (PDT) combines a photosensitizer (protoporphyrin PpIX, induced by the administration of aminolevulic acid, ALA) with activation by visible light, and is a completely nonscarring technique. PDT is approved by the FDA for field treatment of widespread cutaneous precancers, and in European countries PDT is also approved for treating SCC and BCC. In the U.S. however, approval of PDT for SCC and BCC will require further clinical trials to demonstrate an efficacy similar to existing techniques (destructive ablation). As a new way to increase PDT efficacy, we showed that in animal models of SCC and BCC, transient administration of Vitamin D (VD) prior to ALA-PDT enhances PpIX accumulation and PDT efficacy. The oral (dietary) form of VD (cholecalciferol; D3, given as 10,000 IU/day for 10 days) increases PDT-induced tumor killing by several fold, and is very safe with little risk for inducing hypercalcemia. In this grant, we propose to test this approach in human clinical trials using oral D3 as a neoadjuvant to PDT. Aim 1 will examine the relationship between VD status (serium 25OH-D3) and PDT efficacy for CIS. Subaim 1a is a longitudinal study to test the correlation between serum 25OH-D3 levels and treatment outcomes in routine PDT patients in our clinics, and to examine the predictive value of certain biomarkers (e.g. VDR allelic polymorphisms). Subaim 1b is an interventional trial to assess the benefit of giving neoadjuvant D3 (transient oral D3) prior to PDT. Results from combined D3/PDT treatment (Subaim 1b) will be compared to results after D3 alone (Subaim 1a), stratified by the VD deficiency status. In Aim 2, we will examine the potential benefit of neoadjuvant D3/PDT in patients with BCNS (Gorlin-Goltz syndrome). These patients, who have multiple BCC tumors will receive 3 bimonthly PDT treatments, and rates of tumor shrinkage will be correlated with serum 25OH-D3 levels. Each patient will serve as his/her own control by randomizing the order of the first two PDT treatments, one session to be done with neoadjuvant D3 and the other without. The third PDT treatment will occur after the serum VD level has been adjusted to normal levels with D3 supplements. This approach will allow us to determine whether neoadjuvant D3/PDT can help all patients, even the VD deficient individuals, through customization of D3 dose. Together, we expect this group of clinical trials to establish the foundation for a new treatment modality, i.e., neoadjuvant D3/PDT for skin cancer. The potential benefit for public health is that data showing improved efficacy of PDT with this safe and simple approach will lay the foundation for a nonscarring alternative to surgery for early SCC and BCC tumors.