Signal and Transcription Factor Network interactions in Head and Neck Cancer

我们先前发现头颈部鳞状细胞癌（HNSCC）中NF-κ B相关基因的过表达、TGF β受体（TBR）亚单位的表达改变和下游靶点之间存在相关性。在前一年期间，我们报道了TGF β受体I/磷酸酶张力蛋白（Tgfbr 1/Pten）在HNSCC中经常降低，并且这些基因的条件性双敲除小鼠发展出表现出增加的PI 3 K-Akt途径和NF-κ B/REL活化的HNSCC（Bian，Oncogene，2012）。我们报道了PI 3 K-mTOR抑制剂用于预防这些Tgfbr 1/Pten dko小鼠中的肿瘤发展和治疗携带人异种移植物的小鼠的潜力（Herzog，Bian等人，Clin Cancer Res，2013）。我们发现PI 3 K-mTOR拮抗剂抑制下游促生长信号传导，重新激活肿瘤抑制因子TP 53，并使肿瘤对细胞毒性化疗和放疗敏感。 作为与NIDCR研究人员合作的NIH主任Bench to Bedside奖的共同获得者，我们正在进行一项新辅助mTOR抑制剂雷帕霉素在晚期HNSCC患者中的初步临床研究（NIH方案10-D-180）。迄今为止，已累积了10名受试者。 热休克蛋白90抑制剂靶向许多癌蛋白的信号网络，我们已经表明，在HNSCC共激活。在合作研究中，我们最近报道了HSP 90抑制剂靶向过表达的表皮生长因子受体、下游信号传导，并强烈抑制人HNSCC异种移植物（Ahsan等人，Neoplasia，2012）。我们报道了在NIH的I期研究中，HSP 90抑制剂SNX 5422/2112广泛抑制致癌信号和转录因子，并在人HNSCC系和肿瘤异种移植模型中重新激活野生型p53（Friedman等人，Translational Oncol，2013）。 炎症和炎性信号传导涉及促进癌症发展，包括人头颈部鳞状细胞癌（HNSCC）。我们最近证明，NF-κ B转录因子c-REL与TP 53家族成员DeltaNp 63和TAp 73相互作用，以抑制炎症和癌症相关基因，同时抑制HNSCC中的生长停滞和促凋亡基因（Lu，Cancer Res，2011; Yang，Cancer Res，2011）。总之，这些研究结果表明，信号调节协调NF-κ B，p63和p73的相互作用和功能可能是重要的发病机制，并作为预防和治疗的目标。在SCC癌症干细胞中调节NF-κ B和TAp 73的候选激酶已被鉴定为潜在的治疗靶点。

We previously found an association between overexpression of NF-kB related genes, altered expression of TGFb receptor (TBR) subunits and downstream targets in head and neck squamous cell carcinoma (HNSCC). During the prior year we reported that TGFbeta receptor I/ phosphastase tensin (Tgfbr1/Pten) are frequently decreased in HNSCC, and conditional double knockout mice for these genes develop HNSCC that exhibit increased PI3K-Akt pathway and NF-kappaB/REL activation (Bian, Oncogene, 2012). We report the potential of PI3K-mTOR inhibitor for prevention of tumor development in these Tgfbr1/Pten dko mice and therapy of human xenograft bearing mice (Herzog, Bian et al., Clin Cancer Res, 2013). We found that PI3K-mTOR antagonist inhibited downstream progrowth signaling, reactivated tumor suppressor TP53, and sensitized tumors to cytotoxic chemotherapy and radiation. As co-recipients of an NIH Director's Bench to Bedside Award in collaboration with NIDCR investigators, we are conductinga pilot clinical study of neoadjuvant mTOR inhibitor rapamycin in patients with advanced HNSCC (NIH protocol 10-D-180). 10 subjects have been accrued to date. Heat Shock Protein 90 inhibitors target many oncoproteins in the signal network we have shown is co-activated in HNSCC. In collaborative studies, we recently reported that HSP90 inhibitors target overexpressed Epidermal growth factor receptor, downstream signaling, and strongly inhibit human HNSCC xenografts (Ahsan et al., Neoplasia, 2012). We report that HSP90 inhibitor SNX5422/2112 in phase I studies at NIH broadly inhibited oncogenic signal and transcription factors and reactivates wild type p53 in human HNSCC lines and tumor xenograft models (Friedman et al., Translational Oncol, 2013). Inflammation and inflammatory signaling is implicated in promoting cancer development, including human head and neck squamous cell carcinomas (HNSCC). We recently demonstrated that NF-kB transcription factor c-REL interacts with TP53 family members DeltaNp63 and TAp73 to reciprocally activate inflammatory and cancer related genes, while repressing growth arrest and proapoptotic genes in HNSCC (Lu, Cancer res, 2011; Yang, Cancer Res, 2011). Together, these findings suggest signal regulation coordinating NF-kB, p63 and p73 interactions and function may be important in pathogenesis and as targets for prevention and therapy. Candidate kinases regulating NF-kB and TAp73 in SCC cancer stem cells has been identified as potential targets for therapy.