Role of p53 and ptc tumor suppressive pathways in BCCs development and prevention

描述（由申请方提供）：太阳紫外线B（UVB）辐射是非黑色素瘤皮肤癌（NMSC）（包括鳞状细胞癌（SCC）和基底细胞癌（BCC））诱导和发展的主要风险因素，在美国每年有超过100万例新诊断的人类癌症。UVB引起DNA结构改变，导致肿瘤抑制基因（如BCC中的p53和ptch）和这些病变周围皮肤中的热点突变。这些肿瘤的发病机制被认为是由音刺猬（shh）信号传导的突变激活和p53的失活驱动的，导致细胞凋亡的阻断和细胞增殖的增强以及引发细胞的克隆扩增，从而促进BCC的生长。在这个建议中，我们将测试的假设，shh激活和p53抑制的组合驱动的肿瘤过程中的基底细胞癌，并发现有针对性地阻断UVB对这些信号通路的影响的化学试剂将废除这些病变的发展。在这项研究中，我们将采用基因工程的癌症易感小鼠模型，模拟肿瘤易感人类皮肤的表型。其中包括：携带p53+/+p53+/-或p53-/-的ptc 1+无毛小鼠;在先前的研究中，我们已经表明，除了横纹肌肉瘤外，携带p53+/+的ptc 1 +/SKH 1无毛小鼠还自发地发生多种人类BCC样病变。这些小鼠皮肤的慢性UVB照射容易诱导多种肿瘤，包括乳头状瘤、SCC和BCC，提供了独特相关的人皮肤癌诱导的鼠模型。在这种小鼠模型中，我们将研究靶向抗癌剂包括环巴胺和CP-31398的作用，它们分别阻断shh活化和将突变型p53转化为功能活性蛋白。我们还将评估核因子κ B（NF κ B）的作用，NF κ B也是由UVB照射皮肤诱导的，使用柳氮磺胺吡啶通过直接抑制Ik B激酶来阻断NF κ B活化。采用LC-MS，我们已经表明，共同给予环巴胺和CP-31398或柳氮磺胺吡啶不会改变个别药剂的生物利用度。我们相信，这些研究将形成转化临床试验的基础，从而这些测试试剂的合适组合可以证明在废除BCC方面非常有效，并且可以为易感人群中NMSC的化学预防提供基于机制的独特有效方法。

DESCRIPTION (provided by applicant): Solar ultraviolet B (UVB) radiation is the major risk factor for the induction and development of non-melanoma skin cancer (NMSC) including squamous cell carcinoma (SCCs) and basal cell carcinoma (BCCs) which account for more than one million newly diagnosed human cancers annually in the USA. UVB causes structural alterations in DNA leading to hot spot mutations in tumor suppressor genes such as p53 and ptch in BCCs and in the perilesional skin surrounding these lesions. The pathogenesis of these tumors is thought to be driven by mutational activation of sonic hedgehog (shh) signaling and inactivation of p53 resulting in blockade of apoptosis and augmentation of cell proliferation and clonal expansion of initiated cells prompting the growth of BCCs. In this proposal we will test the hypothesis that the combination of shh activation and p53 inhibition drives the neoplastic process in BCCs and that finding chemical agents targeted to blocking the effects of UVB on these signaling pathways will abrogate the development of these lesions. For this study we will employ genetically engineered cancer-susceptible murine models that mimic the phenotype of tumor-susceptible human skin. These include: ptc1+ hairless mice carrying p53+/+p53+/- or p53-/-; in prior studies we have shown that ptc1+/SKH1 hairless mice carrying p53+/+ spontaneously develop multiple human BCCs-like lesions in addition to rhabdomyosarcomas. Chronic UVB irradiation of the skin of these mice readily induces multiple tumors including papillomas, SCCs and BCCs, providing a uniquely relevant murine model of human skin cancer induction. In this murine model we will investigate effects of targeted anti-cancer agents including cyclopamine and CP-31398, which block shh activation and convert mutant p53 into a functionally active protein respectively. We will also assess the role of nuclear factor kappa B (NFkB), which is also induced by UVB irradiation of the skin, by using sulfasalazine that blocks NFkB activation by directly inhibiting IkB kinases. Employing LC-MS, we have shown that co-administration of cyclopamine and CP-31398 or sulfasalazine does not alter individual agent's bioavailability. It is our belief that these studies will form the basis for translational clinical trials whereby a suitable combination of these test agents could prove highly effective in abrogating BCCs and may provide a mechanism-based uniquely effective approach for the chemoprevention of NMSCs in susceptible human populations.