Post-transplant Cutaneous Squamous Cell Carcinoma and Macrophage Migration Inhibitory Factor

 描述(申请人提供)：紫外线B(UVB；290-320 nm)是一种主要的环境致癌物质，与基底细胞癌(BCC)和鳞状细胞癌(SCC)的发展有关，统称为非黑色素瘤皮肤癌(NMSC)。正如最近卫生局局长的行动呼吁所强调的那样，这些皮肤肿瘤是人类最常见的癌症形式，每年在美国发现超过350万新病例。据最近估计，2012年美国有3932至8791人死于皮肤鳞状细胞癌，略低于黑色素瘤的死亡人数。在免疫抑制人群中，如实体器官移植受者(OTR)的死亡率大大增加。在这些患者中，与非免疫抑制患者相比，鳞状细胞癌的发生率要高得多。器官移植使发生鳞癌的风险增加65-200倍。事实上，“灾难性皮肤癌病”这个术语已经被创造出来，用来描述这些患者的鳞状细胞癌的发展。灾难性皮肤癌的病例可能需要减少免疫抑制治疗，从而冒着失去移植器官的风险。在免疫能力强的人群中，性起着重要的作用，免疫抑制的男性患鳞癌的风险比女性更大。显然，需要更有效的预防和/或治疗策略，以防止这些患者因鳞状细胞癌的发展而导致的发病率和死亡率。巨噬细胞移动抑制因子(MIF)是一种免疫调节细胞因子，在人类黑色素瘤和头颈部鳞状细胞癌等多种肿瘤中过表达。我们已经在免疫活性的MIF、KO和在慢性UVB暴露后用药物MIF抑制剂(MIFI)治疗的野生型小鼠中证明了这种细胞因子同样有助于UVB诱导的皮肤SCC的发展。到目前为止，我们还不知道有任何研究考察了免疫抑制疗法对皮肤MIF水平的影响。当前应用中的研究将使用这一临床前模型来检验以下假设 在OTR中观察到的UVB诱导的SCC增加至少部分是通过皮肤MIF水平的升高来调节的。Aim 1的研究将使用临床前的Skh-1小鼠模型来确定在开始免疫抑制治疗之前使用MiFi治疗对UVB诱导的两性肿瘤发展的疗效。AIM 2的研究将确定MiFi治疗在免疫抑制环境下诱导两性已建立的肿瘤消退的有效性。这些研究的完成将为口腔癌的灾难性皮肤癌病提供新的干预/治疗策略的重要信息。

 DESCRIPTION (provided by applicant): Ultraviolet light B (UVB; 290-320 nm) is a major environmental carcinogen that has been implicated in the development of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), collectively known as nonmelanoma skin cancers (NMSC). As highlighted by the recent Surgeon General's Call to Action, these skin tumors are the most common form of cancer in humans, with over 3.5 million new cases identified in the United States each year. It was recently estimated that between 3932 and 8791 individuals died from cutaneous SCC in the United States in 2012, just slightly fewer than deaths from melanoma. The mortality rate greatly increases in the immunosuppressed population such as solid organ transplant recipients (OTR). In these patients SCC is vastly over-represented compared with its frequency in non-immunosuppressed patients. Organ transplantation increases the risk of development of SCC by 65-200 fold. In fact the term "catastrophic cutaneous carcinomatosis" has been coined to describe the development of SCCs in these patients. Cases of catastrophic cutaneous carcinomatosis may require decreasing immunosuppressive therapy risking the loss of the transplanted organ. As seen in the immunocompetent population, sex plays a strong role, with immunosuppressed men having greater risk of developing SCC than women. Clearly more effective preventive and/or treatment strategies are needed to prevent the morbidity and mortality resulting from SCC development in these patients. Macrophage migration inhibitory factor (MIF) is an immunoregulatory cytokine that is overexpressed in several cancers including melanoma and head/neck SCC in humans. We have demonstrated in immune competent MIF KO and wild type mice treated with a pharmacological MIF inhibitor (MIFi) following chronic UVB exposure that this cytokine likewise contributes to the development of UVB- induced SCC of the skin. To date we are not aware of any studies examining the effects of immunosuppressive therapies on cutaneous levels of MIF. The studies in the current application will use this pre-clinical model to test the hypothesis that increases in UVB-induced SCC observed in OTR are mediated at least in part by elevated cutaneous MIF levels. Studies in Aim 1 will use the preclinical Skh-1 murine model to determine the efficacy of therapeutic intervention with a MIFi prior to the initiation of immunosuppressive therapy on UVB induced tumor development in the sexes. Studies in Aim 2 will determine the efficacy of MIFi treatment in inducing regression of established tumors in the sexes under an immunosuppressive environment. Completion of these studies will provide important information about a novel intervention/treatment strategy for catastrophic cutaneous carcinomatosis in OTR.