The Regulation of Apoptosis by Cooperative Src and MAPK Signaling in Thyroid Cancer

甲状腺癌中 Src 和 MAPK 信号协同调节细胞凋亡

• 批准号: 10092807
• 负责人: Madison Mariah King Rose
• 金额: $ 3.89万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092807
• 关键词: Apoptosis; Apoptotic; BCL2L11 gene; BIM Bcl-2-binding protein; BRAF gene; Biosensor; Cancer Patient; Cell Line; Cells; Cessation of life; Clinic; Clinical; Combined Modality Therapy; Dasatinib; Disease; Distant Metastasis; Goals; Growth; In Vitro; Induction of Apoptosis; Injections; MAP Kinase Gene; MAP2K1 gene; MEK inhibition; MEKs; Malignant neoplasm of thyroid; Mass Spectrum Analysis; Measures; Mediating; Mediator of activation protein; Metastasis Induction; Mission; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mutation; National Cancer Institute; Neoplasm Metastasis; PI3K/AKT; PIK3CA gene; PTK2 gene; Papillary thyroid carcinoma; Pathway interactions; Patients; Phase; Phosphoproteins; Phosphorylation; Prognosis; Property; Protein Array; Protein Tyrosine Kinase; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Research; Research Training; Resistance; Role; Science; Signal Induction; Signal Transduction; Site; Solid Neoplasm; Structure; Survival Rate; Thyroid Gland; Treatment Efficacy; Tyrosine; Tyrosine Phosphorylation; anaplastic thyroid cancer; anticancer research; antitumor effect; cancer cell; carcinogenesis; cellular engineering; chemotherapeutic agent; chemotherapy; clinically relevant; driver mutation; effective therapy; in vivo; inhibitor/antagonist; knock-down; mutant; novel; novel therapeutic intervention; overexpression; pro-apoptotic protein; response; response biomarker; src-Family Kinases; success; targeted agent; targeted treatment; tumor; tumor growth; tumor heterogeneity; tumor progression; tumorigenesis; tumorigenic

Project Summary/Abstract: Advanced thyroid cancer patients continue to have dismal prognosis and poor survival ratees due to lack of effective therapies. While the MAPK pathway accounts for a majority of the mutations that arise in thyroid cancer (BRAF, RAS, RET/PTC), targeting this pathway has had mixed success in the clinic. The recent approval of a BRAF inhibitor in combination with a MEK1/2 inhibitor for anaplastic thyroid cancer patients (ATC) with a BRAF V600E mutation is monumental, however, this combination is only effective in subset of ATC patients, and is ineffective in BRAF-mutant papillary thyroid cancer (PTC) patients; highlighting the necessity to identify new therapeutic strategies for patients who do not respond to current therapies. Our lab has discovered Src as a clinically relevant target in thyroid cancer and we have demonstrated that Src inhibition with two structurally independent Src inhibitors, dasatinib and saracatinib, inhibits growth, invasion, and metastasis. However, like many single-agent targeted therapies, clinical responses to single-agent Src inhibition has been limited in solid tumors, indicating combination therapies will be necessary. Accordingly, recent studies have shown that the Src inhibitor, dasatinib, in combination with chemotherapeutic agents has clinical benefit, thus supporting the rationale to identify targets that can be co-inhibited with Src. To this end, our lab has demonstrated that co-inhibition of Src and MEK1/2 synergizes to inhibit growth, increase survival, and induce apoptosis in BRAF- and RAS-mutant thyroid cancer cells, while PIK3CA-mutant cells were shown to be resistant to this combination. To begin to decipher mechanism(s) mediating sensitivity in response to combined Src and MEK1/2 inhibition, I used a reverse phase protein array (RPPA) of >400 proteins and phosphoproteins and identified the pro-apoptotic protein, BIM, as a potential mediator of response. Therefore, the goals of my proposal are to determine the regulation of apoptosis by cooperative Src and MAPK signaling in thyroid cancer. Specifically, in Aim 1 I will determine the regulation and role of PI3K/AKT-dependent signaling in mediating the apoptotic response, in Aim 2 I will determine the mechanism(s) of apoptosis regulated by Src and MAPK signaling, and finally in Aim 3, I will determine the role of combined Src and MEK1/2 inhibition on tumor growth, metastasis, and the induction of apoptosis in vivo. This proposal emphasizes a molecular understanding of mechanisms mediating response to Src and MEK1/2 inhibition to develop new strategies to enhance these effects and potential approaches to sensitize resistant tumors. The completion of the proposed research will help the National Cancer Institute fulfill their mission to support cancer research and training in the fundamental sciences.

项目概要/摘要： 晚期甲状腺癌患者的预后仍然很差， 有效的治疗。虽然MAPK途径占甲状腺癌中出现的大多数突变， 癌症（BRAF、RAS、RET/PTC），靶向该途径在临床上取得了好坏参半的成功。近期 批准BRAF抑制剂与MEK 1/2抑制剂联合治疗未分化甲状腺癌患者 (ATC)与BRAF V600 E突变是巨大的，然而，这种组合只在亚组有效 ATC患者，并且在BRAF突变型乳头状甲状腺癌（PTC）患者中无效;强调了 有必要为对当前疗法无反应的患者确定新的治疗策略。我们实验室 已经发现Src是甲状腺癌的临床相关靶点，我们已经证明Src 用两种结构上独立的Src抑制剂达沙替尼和萨拉替尼抑制生长，侵袭， 和转移。然而，与许多单药靶向治疗一样，单药Src 抑制作用在实体瘤中受到限制，这表明联合治疗是必要的。因此，委员会认为， 最近的研究表明，Src抑制剂达沙替尼与化疗药物联合使用， 临床受益，因此支持确定可与Src共抑制的靶点的依据。为此目的， 我们的实验室已经证明Src和MEK 1/2的共抑制协同抑制生长，增加存活， 并诱导BRAF和RAS突变型甲状腺癌细胞凋亡，而PIK 3CA突变型细胞显示 能够抵抗这种组合。开始破译响应的敏感性介导机制 结合Src和MEK 1/2抑制，我使用了>400种蛋白质的反相蛋白质阵列（RPPA）， 磷蛋白，并确定了促凋亡蛋白，BIM作为一个潜在的调解人的反应。因此，我们认为， 我的研究目标是确定Src和MAPK信号协同作用对细胞凋亡的调节作用 在甲状腺癌中。具体而言，在目标1中，我将确定PI 3 K/AKT依赖性的调节和作用。 在介导细胞凋亡反应的信号传导中，目的2中，I将确定细胞凋亡的机制 由Src和MAPK信号调节，最后在目标3中，我将确定Src和MAPK信号结合的作用。 MEK 1/2在体内抑制肿瘤生长、转移和诱导细胞凋亡。这项建议 强调了对Src和MEK 1/2抑制的介导反应机制的分子理解， 开发新的策略来增强这些效果和潜在的方法来敏化耐药肿瘤。的 完成拟议的研究将有助于国家癌症研究所履行其使命， 癌症研究和基础科学培训。