aPKC function in Hedgehog signaling and basal cell carcinoma

描述（由申请人提供）：基底细胞癌（BCC）是世界上最常见的癌症，近一半的美国公民可能在退休前患上这种癌症。bcc是一种侵袭性上皮肿瘤，起源于Hedgehog （Hh）通路的激活突变，这是一种重要的发育通路，与大约25%的人类癌症死亡有关。尽管Hh信号的关键性质，但Hh如何介导癌症中令人印象深刻的增殖缺陷仍然知之甚少。Hh通路激活始于Hh配体结合并抑制跨膜受体Patched1，允许信号换能器Smoothened （Smo）激活Gli转录因子并扩增Hh靶基因的表达。Smo抑制剂最近被批准用于治疗晚期或转移性BCC，并表现出有效的肿瘤消退。虽然这些抑制剂对naïve肿瘤有效，但侵袭性肿瘤往往会对药物产生早期耐药性，这表明需要新的治疗靶点。我最近发现一个非常重要的癌基因，非典型蛋白激酶C iota/ λ (aPKC-ι/λ)，在几乎所有多细胞生物的发育过程中参与干细胞命运的选择，对于bcc中高水平、持续的Hh通路激活至关重要。我也证明了aPKC的药理学抑制可以抑制小鼠

DESCRIPTION (provided by applicant): Basal cell carcinoma (BCC) is the most prevalent cancer in the world and nearly half of US citizens are likely to develop this cancer before retirement. BCCs are invasive epithelial tumors that originate from activating mutations in the Hedgehog (Hh) pathway, an essential developmental pathway that has been implicated in approximately 25% of all human cancer deaths. Despite the critical nature of Hh signaling, how Hh mediates the impressive proliferative defects in cancers remain poorly understood. Hh pathway activation begins when Hh ligand binds and inhibits transmembrane receptor Patched1, allowing signal transducer Smoothened (Smo) to activate Gli transcription factors and amplify expression of Hh target genes. Smo inhibitors have recently gained approval for treatment of late advanced or metastatic BCC and exhibit potent tumor regression. While these inhibitors are effective in naïve tumors, aggressive tumors tend to develop early resistance to the drug, illustrating the need for new therapeutic targets. I have recently discovered that a critically important oncogene, atypical Protein Kinase C iota/lambda (aPKC-ι/λ), involved in stem cell fate choice during development of nearly all multicellular organisms is essential for high, sustained Hh pathway activation in BCCs. I have also shown pharmacological inhibition of aPKC suppresses murine BCC tumor growth and the growth of naïve and Smo-resistant BCC cells. The goal of my research is to determine the mechanisms that allow the polarity protein aPKC-ι/λ to promote Hh pathway activation and naïve and Smo-resistant BCC growth. During the K99 phase, I will determine how phosphorylation of Gli by aPKC-ι/λ alters target gene specificity to promote tumor growth, how BCC's regulate aPKC-ι/λ activity, and test the therapeutic potential of additional novel aPKC-ι/λ inhibitors for the treatment of naïve and resistant BCC. During the R00 phase, I will determine how aPKC-ι/λ-dependent Gli1 responsive genes regulate tumor invasion and analyze aPKC-ι/λ function in Smo-resistant BCCs. The results of this study will reveal conserved mechanisms that govern cell polarity and Hh signaling during BCC that will prove invaluable in generating novel therapeutics for the treatment of Hh-dependent cancers.