Oral Vitamin D3 and Photodynamic Therapy of Epithelial Cancers

描述（由申请人提供）：皮肤癌，包括鳞状细胞癌（SCC）和基底细胞癌（BCC），是所有人类癌症中最常见的。虽然很少致命，但皮肤癌对医疗保健系统来说是一个巨大的经济负担（排名第五，仅次于乳腺癌、结肠癌、肺癌和前列腺癌）。此外，皮肤癌的手术治疗往往会导致难看的、肥厚的疤痕。光动力疗法（PDT）是一种针对癌细胞的无疤痕治疗，分为两步：(1)光敏药物的肿瘤选择性积累，(2)强可见光照射。最常用的PDT方案使用氨基乙酰丙酸（ALA）作为前药，它被肿瘤细胞选择性地吸收并转化为原卟啉IX (PpIX)；后者是吸收光的实际光敏剂。尽管PDT在欧洲国家被广泛接受用于治疗鳞状细胞癌和基底细胞癌，由于其良好的美容效果和较低的成本，美国FDA批准的PDT唯一的用途是用于治疗癌前病变（光化性角化病）。造成这种情况的一个原因是，除了美国医生使用低报销模式的经济动机不佳外，PDT治疗深部结节性基底细胞癌或侵袭性鳞状细胞癌不如手术切除有效。作为一种提高ALA-PDT疗效的方法，我们最近在小鼠SCC肿瘤中发现，用维生素D3 （VD3）的活性形式骨化三醇预处理，可以改善PpIX的积累，增强ALA-PDT的肿瘤特异性杀伤。然而，骨化三醇的方法有一个潜在的问题，因为如果骨化三醇过量，会引起毒性（高钙血症）。为了避免这种情况，我们有初步的数据表明，作为短期膳食补充剂的胆骨化醇（D3）实际上可以显著促进皮肤肿瘤中PpIX的产生，其程度几乎与全身预处理骨化三醇相同，但没有高钙血症的风险。当前提案的总体目标是测试口服维生素D3（胆钙化醇）与PDT （cPDT）联合使用是否是一种安全可行的方法来提高治疗皮肤癌的疗效。两个实验目的将在皮肤SCC（人类异种移植）和基底细胞癌（小鼠BCC）的小鼠模型中进行。目的1将确定口服D3在肿瘤组织中引起特异性PpIX积累的机制。实验将测试血清25-OH D3向骨化三醇的转化是否发生在皮肤肿瘤局部，以及PpIX诱导是否需要维生素D受体（VDR）。目的2将建立口服D3的适当剂量范围和时间过程，以实现安全有效的PpIX光敏。此外，由于已知大多数美国人缺乏维生素D3， Aim 2将询问基线维生素D3缺乏状态是否会影响给药胆骨化醇提高PpIX水平和PDT疗效的能力。这项工作的成功完成将提供足够的信息来指导未来治疗鳞状细胞癌、基底细胞癌和转移上皮癌患者的临床试验的设计。对公众健康的潜在好处将是一种安全、有效、无疤痕的癌症手术治疗替代方案。

DESCRIPTION (provided by applicant): Skin cancers, including squamous cell (SCC) and basal cell carcinoma (BCC), are the most common of all human cancers. Although seldom lethal, skin cancers are a huge economic burden to the healthcare system (fifth most expensive, behind breast, colon, lung, and prostate cancer). In addition, surgical treatment of skin cancer often leads to unsightly, hypertrophic scars. Photodynamic Therapy (PDT) is a non-scarring treatment that targets cancer cells in a two step process: (1) the tumor-selective accumulation of a photosensitizing drug, and (2) illumination with strong visible light. The PDT regimen most frequently employed uses aminolevulinic acid (ALA) as a prodrug, which is selectively taken up by tumor cells and converted into protoporphyrin IX (PpIX); the latter is the actual photosensitizer that absorbs light. Despite widespread acceptance of PDT in European countries for treating SCC and BCC, due to its good cosmetic results and lower costs, the only FDA- approved use of PDT in the U.S.A. is for the treatment of pre-cancers (actinic keratoses). One reason for this, aside from poor economic incentives for U.S. physicians to use a lower-reimbursing modality, is the fact that PDT is not quite as effective as surgical excision for deep nodular BCC or invasive SCC. As a way to improve ALA-PDT efficacy, we recently showed in SCC tumors in mice that pretreatment with calcitriol, the active form of Vitamin D3 (VD3), improves PpIX accumulation and enhances tumor-specific killing by ALA-PDT. The approach with calcitriol has a potential problem, however, because calcitriol, if overdosed, can cause toxicity (hypercalcemia). To circumvent this, we have preliminary data to show that cholecalciferol (D3) as a short-term dietary supplement can in fact significantly boost production of PpIX in skin tumors, to nearly the same extent as systemic pretreatment with calcitriol, but without the hypercalcemic risk. The overall goal of the current proposal is to test whether oral Vitamin D3 (cholecalciferol), used in a combination approach with PDT (cPDT), is a safe and viable way to enhance the efficacy of treatment for skin cancer. Two experimental aims will be pursued in mouse models of cutaneous SCC (human xenograft) and basal cell carcinoma (murine BCC). Aim 1 will determine the mechanisms by which oral D3 causes specific PpIX accumulation in the tumor tissue. Experiments will test whether conversion of serum 25-OH D3 to calcitriol occurs locally in skin tumors, and whether the Vitamin D receptor (VDR) is required for PpIX induction. Aim 2 will establish the proper dose range and time course for oral D3 to achieve safe and effective PpIX photosensitization. In addition, since the majority of people in the U.S.A. are known to be Vitamin D3 deficient, Aim 2 will ask whether a state of baseline VD3 deficiency affects the ability of administered cholecalciferol to enhance PpIX levels and PDT efficacy. Successful completion of this work should provide sufficient information to guide the design of future clinical trials designed to treat patients with SCC, BCC, and metastatic epithelia carcinomas. The potential benefit to public health would be a safe, effective, non-scarring alternative to surgery for treatment of cancer.