Targeting c-Src in Head and Neck Cancer

描述（由申请人提供）：头颈部鳞状细胞癌（HNSCC）的靶向Src激酶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，如语言和吞咽，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，并与较差的局部控制和较低的生存率相关。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。在HNSCC中，一个很有前景的分子靶点是c-Src。抑制c-Src可显著抑制HNSCC细胞的迁移和侵袭；然而，c-Src抑制的细胞毒性作用难以预测。明确限制c-Src抑制剂细胞毒性作用的机制，可能会导致HNSCC治疗药物的理想组合，既抑制局部侵袭，又导致显著的细胞毒性。由于STATs可以介导c-Src下游的增殖和存活，我们研究了STATs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，从而导致STAT3的再激活。我们研究了导致STAT3激活的反馈通路，发现c-Src抑制导致细胞因子信号传导抑制因子2 （SOCS2）的下调，SOCS2是JAK/STAT3的负调节因子。阻断这一反馈通路可显著增强c-Src抑制的细胞毒作用。我们假设持续的c-Src激酶抑制通过涉及SOCS2的新反馈途径导致JAK/STAT3再激活，并且抑制该反馈途径将增强c-Src抑制的治疗效果。我们将以三个具体目标来验证这一假设：阐明HNSCC中c-Src持续抑制后导致STAT3激活的反馈回路的机制；评估JAK抑制是否能增强c-Src抑制剂达沙替尼在HNSCC原位模型中的治疗效果；并开发和表征HNSCC的异源移植模型，以测试c-Src和JAK抑制的生物学和信号效应。在后一个目标中，我们将在一种新的患者来源的异源移植模型中评估反馈通路，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HNSCC患者的未来临床试验，该试验将测试双重靶向JAK和c-Src抑制的有效性，以改善这种致命疾病的治疗选择。

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.