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

项目总结/摘要 基底细胞癌（BCC）、鳞状细胞癌（SCC）和原位鳞状癌前病变（CIS，也称为原位鳞状细胞癌）。 称为光化性角化病）是所有人类肿瘤中最常见的，并且显著地促成了 国家医疗负担。虽然现有的技术，例如冷冻消融或手术切除， 治疗，这些治疗会导致疤痕，特别是在皮肤高风险患者的毁容， 癌症（即，患有慢性严重光损伤的患者;由于器官移植导致的免疫抑制;或 基底细胞痣综合征，BCNS）。光动力疗法（PDT）结合光敏剂 （原卟啉PpIX，通过给予氨基酮戊酸（ALA）诱导），通过可见光活化， 而且是一种完全无疤痕的技术。PDT已被FDA批准用于广泛的 皮肤癌前病变，并且在欧洲国家PDT也被批准用于治疗SCC和BCC。在 美国然而，批准PDT治疗SCC和BCC还需要进一步临床试验来证明其疗效， 类似于现有技术（破坏性消融）。作为一种提高PDT疗效的新方法，我们发现， SCC和BCC的动物模型，在ALA-PDT之前暂时给予维生素D（VD）增强PpIX 积累和PDT功效。口服（饮食）形式的VD（胆钙化醇; D3，以10，000 IU/天给药， 10天）使PDT诱导的肿瘤杀伤增加数倍，并且非常安全，诱导肿瘤的风险很小。 高钙血症在这项资助中，我们建议在人类临床试验中使用口服D3作为一种药物来测试这种方法。 PDT的新辅助治疗。目的1将研究VD状态（血清25 OH-D3）与PDT之间的关系 CIS的功效。Subaim 1a是一项纵向研究，旨在检测血清25 OH-D3水平与 在我们的诊所常规PDT患者的治疗结果，并检查某些 生物标志物（例如VDR等位基因多态性）。Subaim 1b是一项干预性试验，旨在评估 在PDT之前给予新辅助D3（短暂口服D3）。D3/PDT联合治疗的结果（Subaim 1b） 将与单独D3（Subaim 1a）后的结果进行比较，按VD缺乏状态分层。在目标2中，我们将 检查新辅助D3/PDT在BCNS（Gorlin-Goltz综合征）患者中的潜在获益。这些 患有多个BCC肿瘤的患者将接受3次双月PDT治疗，肿瘤缩小率 将与血清25 OH-D3水平相关。每例患者将通过随机化作为其自身对照 前两次PDT治疗的顺序，一次使用新辅助D3，另一次不使用。 第三次PDT治疗将在用D3将血清VD水平调整至正常水平后进行 补充剂.这种方法将使我们能够确定新辅助D3/PDT是否可以帮助所有患者， 甚至VD缺陷个体，通过定制D3剂量。我们共同期待这组临床 试验为新的治疗方式奠定基础，即，新辅助D3/PDT治疗皮肤癌。的 对公众健康的潜在益处是，数据显示，使用这种安全简单的方法， 该方法将为早期SCC和BCC肿瘤的无瘢痕替代手术奠定基础。

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.