Stat3 as a Therapeutic Target in Head and Neck Cancer

Stat3 作为头颈癌的治疗靶点

• 批准号: 6828135
• 负责人: Jennifer Rubin Grandis
• 金额: $ 27.23万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6828135
• 关键词: DNA binding protein; antineoplastics; athymic mouse; biological signal transduction; biotherapeutic agent; clinical research; drug delivery systems; drug design /synthesis /production; drug screening /evaluation; epidermal growth factor; gene expression; growth factor receptors; head /neck neoplasm; human tissue; immunocytochemistry; intracellular transport; method development; oligonucleotides; pharmacokinetics; phosphorylation; prognosis; protein quantitation /detection; protein structure function; protein transport; squamous cell carcinoma

DESCRIPTION (provided by applicant): Signal Transducers and Activators of Transcription (STATs) are intracellular signaling proteins that are activated upon tyrosine phosphorylation and translocate from the cytosol to the nucleus where they bind to specific regions of DNA and exert transcriptional activity. STAT3 activation has been linked to transformation and tumor progression in several cancers, including squamous cell carcinoma of the head and neck (SCCHN). We have accumulated convincing evidence that constitutive STAT3 activation in SCCHN represents a critical survival pathway in SCCHN. We recently reported that activated STAT3 stimulated SCCHN growth independent of upstream growth factor receptors including EGFR. Further investigation demonstrated that activated STAT3 could be selectively targeted with a double stranded "decoy" oligodeoxynucleotide (ODN) representing the high affinity serum inducible element (hSIE). Blocking activated STAT3 with a STAT3 decoy inhibited SCCHN proliferation and STAT3-mediated gene expression with no effect on the growth of normal mucosal epithelial cells. Therefore, the overall aim of this proposal is to develop a therapeutic strategy that targets activated STAT3, thereby inhibiting SCCHN progression. A transcription factor decoy approach will be optimized to achieve maximal anti-tumor effects, with the ultimate goal of generating a formulation for efficient delivery to human SCCHN cells. To accomplish the goals of this proposal, we will: 1) determine the prognostic significance of activated STAT3 in SCCHN patients; 2) optimize the structure and delivery of the STAT3 decoy to enhance stability and maximize cellular uptake; 3) examine the anti-tumor effects of the STAT3 decoy; and 4) determine the toxicity and pharmacokinetics of optimized STAT3 decoy in preclinical animal models.

描述（由申请人提供）：转录（Stats）的信号换能器和激活因子是细胞内信号蛋白，它们在酪氨酸磷酸化时被激活，并从细胞质转移到细胞核，在那里它们与DNA的特定区域结合并发挥转录活性。 STAT3激活与几种癌症的转化和肿瘤进展有关，包括头颈部鳞状细胞癌（SCCHN）。我们积累了令人信服的证据，即SCCHN中的构型STAT3激活代表了SCCHN中的关键生存途径。我们最近报道，激活的STAT3刺激了SCCHN的生长，与包括EGFR在内的上游生长因子受体无关。进一步的研究表明，活化的STAT3可以通过代表高亲和力诱导元素（HSIE）的双链“诱饵”寡脱氧核苷酸（ODN）选择性地靶向。用STAT3诱饵阻断活化的STAT3抑制了SCCHN增殖和STAT3介导的基因表达，对正常粘膜上皮细胞的生长没有影响。 因此，该提案的总体目的是制定针对激活STAT3的治疗策略，从而抑制SCCHN的进展。转录因子诱饵方法将被优化，以实现最大的抗肿瘤效应，其最终目标是产生有效递送到人类SCCHN细胞的公式。为了实现该提案的目标，我们将：1）确定SCCHN患者激活STAT3的预后意义； 2）优化STAT3诱饵的结构和递送，以增强稳定性并最大化细胞摄取； 3）检查STAT3诱饵的抗肿瘤作用； 4）确定临床前动物模型中优化STAT3诱饵的毒性和药代动力学。