Targeting c-Src in Head and Neck Cancer

描述（由申请人提供）：靶向头颈癌中的Src激酶头颈鳞状细胞癌（HNSCC）在世界范围内很常见，并且特别难以治疗，因为肿瘤和治疗都可能损害基本功能，如言语和吞咽，并严重改变面部外观。局部浸润是HNSCC发病率和死亡率的关键决定因素，并与局部区域控制较差和生存率降低相关。迫切需要改善全身治疗以治疗局部侵袭和远处转移性疾病。HNSCC中的一个有希望的分子靶点是c-Src，已经开发了新的药物。c-Src的抑制导致HNSCC细胞的迁移和侵袭的显著和普遍抑制;然而，c-Src抑制的细胞毒性作用是不可预测的。定义限制c-Src抑制剂的细胞毒性作用的机制可能导致HNSCC治疗剂的理想组合，其抑制局部侵袭并导致显著的细胞毒性。由于STAT可以介导c-Src下游的增殖和存活，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，通过JAK介导对c-Src抑制剂的抗性，导致STAT 3的重新激活。我们研究了导致STAT 3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（SOCS 2）（JAK/STAT 3的负调节因子）的下调。阻断这种反馈途径显著增强了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SOCS 2的新反馈途径导致JAK/STAT 3再激活，并且该反馈途径的抑制将增强c-Src抑制的治疗功效。我们将用三个具体目标来检验这一假设：阐明HNSCC中持续c-Src抑制后导致STAT 3激活的反馈环的潜在机制;评估JAK抑制是否增强了HNSCC原位模型中c-Src抑制剂达沙替尼的治疗功效;并开发和表征HNSCC的异源移植模型，其中测试c-Src和JAK抑制的生物学和信号传导作用。在后一个目标中，我们将评估一种新的患者来源的异源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物。我们的长期目标是将这些发现转化为未来在HNSCC患者中的临床试验，该试验将测试双重靶向JAK和c-Src抑制的疗效，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）或严重改变的面部外观。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。我们已经鉴定了一个蛋白质家族（非受体酪氨酸激酶Src家族），当被抑制时，可以抑制侵袭并导致癌细胞死亡。本提案的目标是提供策略，以提高头颈癌中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.