Targeting c-Src in Head and Neck Cancer

描述（由申请人提供）：头颈癌中的 Src 激酶靶向头颈鳞状细胞癌（HNSCC）在世界范围内很常见，并且特别难以治疗，因为肿瘤和治疗都会损害基本功能，例如言语和吞咽，并严重改变面部外观。局部侵袭是 HNSCC 发病率和死亡率的关键决定因素，并与较差的局部区域控制和生存率降低相关。迫切需要改进全身治疗以治疗局部侵袭和远处转移性疾病。 c-Src 是 HNSCC 中一个有前景的分子靶标，已开发出新的药物。抑制 c-Src 可显着且普遍地抑制 HNSCC 细胞的迁移和侵袭；然而，c-Src 抑制的细胞毒性作用不太可预测。确定限制 c-Src 抑制剂细胞毒性作用的机制可能会产生一种理想的 HNSCC 治疗药物组合，既能抑制局部侵袭，又能产生显着的细胞毒性。由于 STAT 可以介导 c-Src 下游的增殖和存活，因此我们研究了 STAT 在调节 c-Src 抑制作用中的作用。我们发现了一种新的反馈途径，可通过 JAK 重新激活 STAT3，从而介导对 c-Src 抑制剂的耐药性。我们研究了导致 STAT3 激活的反馈途径，发现 c-Src 抑制导致细胞因子信号传导抑制因子 2 (SOCS2)（JAK/STAT3 的负调节因子）的下调。阻断该反馈途径可显着增强 c-Src 抑制的细胞毒性作用。我们假设持续的 c-Src 激酶抑制通过涉及 SOCS2 的新型反馈途径导致 JAK/STAT3 重新激活，并且抑制该反馈途径将增强 c-Src 抑制的治疗效果。我们将通过三个具体目标来检验这一假设： 阐明 HNSCC 中持续抑制 c-Src 后导致 STAT3 激活的反馈环路的潜在机制；评估 JAK 抑制是否增强 c-Src 抑制剂达沙替尼在 HNSCC 原位模型中的治疗效果；开发并表征 HNSCC 异种移植模型，以测试 c-Src 和 JAK 抑制的生物学和信号传导作用。在后一个目标中，我们将评估一种新型患者来源的异种移植模型中的反馈途径，该模型可以作为人类 HNSCC 治疗研究的更好替代品。我们的长期目标是将这些发现转化为未来针对 HNSCC 患者的临床试验，该试验将测试双靶向 JAK 和 c-Src 抑制的功效，以改善这种致命疾病的治疗选择。 公共卫生相关性：发生在头颈部的癌症在美国很常见，通常会导致死亡或基本功能受损（例如言语和吞咽）或严重改变面部外观。因此，非常需要改善这些肿瘤患者的全身治疗，以提高治愈率并降低发病率。我们已经鉴定出一个蛋白质家族（非受体酪氨酸激酶的 Src 家族），当受到抑制时，可以抑制侵袭并导致癌细胞死亡。该提案的目标是提供策略来增强头颈癌中 Src 蛋白抑制的治疗效果。

DESCRIPTION (provided by applicant): Targeting Src Kinases in Head and Neck Cancer Head and neck squamous cell carcinoma (HNSCC) are common worldwide and are particularly difficult to treat because both the tumor and the treatment can impair essential functions, such as speech and swallowing, and severely alter facial appearance. Local invasion is a critical determinant of both morbidity and mortality for HNSCC and is associated with worse locoregional control and decreased survival. There is a critical need to improve systemic therapy to treat both local invasion and distant metastatic disease. One promising molecular target in HNSCC for which new agents have been developed is c-Src. Inhibition of c-Src causes a significant and universal inhibition of migration and invasion of HNSCC cells; however, the cytotoxic effects of c-Src inhibition are less predictable. Defining mechanisms that limit the cytotoxic effects of c-Src inhibitors may result in an ideal combination of therapeutic agents for HNSCC that inhibits both local invasion and leads to significant cytotoxicity. As STATs can mediate proliferation and survival downstream of c-Src, we studied the role of STATs in modulating the effects of c-Src inhibition. We discovered a novel feedback pathway that leads to the reactivation of STAT3 via JAK which mediates resistance to c-Src inhibitors. We investigated feedback pathways leading to STAT3 activation and found that c-Src inhibition leads to down- regulation of suppressor of cytokine signaling 2 (SOCS2), a negative regulator of JAK/STAT3. Blockade of this feedback pathway significantly enhances the cytotoxic effect of c-Src inhibition. We hypothesize that sustained c-Src kinase inhibition leads to JAK/STAT3 reactivation via a novel feedback pathway involving SOCS2 and that inhibition of this feedback pathway will enhance the therapeutic efficacy of c-Src inhibition. We will test this hypothesis with three specific aims: To elucidate the mechanism underlying the feedback loop leading to STAT3 activation following sustained c-Src inhibition in HNSCC; to evaluate whether JAK inhibition enhances the therapeutic efficacy of the c-Src inhibitor dasatinib in an orthotopic model of HNSCC; and to develop and characterize a heterotransplant model of HNSCC in which to test biologic and signaling effects of c-Src and JAK inhibition. In the latter aim, we will evaluate the feedback pathway in a novel patient-derived heterotransplant model that could serve as a better surrogate for therapeutic studies in human HNSCC. Our long-term goal is to translate these findings into a future clinical trial in HNSCC patients that will test the efficacy of dual-targeting JAK and c-Src inhibition to improve treatment options for this deadly disease. PUBLIC HEALTH RELEVANCE: Cancers that occur in the head and neck region are common in the United States and often result in death or impairment of essential functions (e.g., speech and swallowing) or severely altered facial appearance. Thus, there is a great need to improve systemic therapy for patients with these tumors in order to increase cure rates and reduce morbidity. We have identified a family of proteins (Src family of non-receptor tyrosine kinases) that, when inhibited, can inhibit invasion and lead to cancer cell death. The goal of this proposal is to provide strategies to enhance the therapeutic effects of inhibition of the Src proteins in head and neck cancer.