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.

项目摘要/摘要： 由于缺乏 有效的疗法。而MAPK途径占甲状腺中出现的大部分突变 癌症（BRAF，RAS，RET/PTC），针对该途径的癌症在诊所取得了成功。最近 批准BRAF抑制剂与MEK1/2抑制剂组合用于甲状腺甲状腺癌患者 （ATC）具有BRAF V600E突变是巨大的，但是，这种组合仅在子集中有效 ATC患者，在BRAF突变乳头状甲状腺癌（PTC）患者中无效；突出显示 为对当前疗法反应反应的患者确定新的治疗策略的必要性。我们的实验室 已经发现SRC是甲状腺癌与临床相关的靶标，我们已经证明了SRC 用两种结构独立的SRC抑制剂Dasatinib和Saracatinib抑制，抑制生长，侵袭， 和转移。但是，像许多单一针对目标疗法一样，对单药SRC的临床反应 实体瘤的抑制作用受到限制，表明组合疗法是必要的。因此， 最近的研究表明，SRC抑制剂Dasatinib与化学治疗剂结合 临床益处，因此支持基本原理，以识别可以与SRC共同抑制的靶标。为此， 我们的实验室表明，SRC和MEK1/2的共同抑制协同抑制生长，增加生存率， 并在BRAF和RAS突变甲状腺癌细胞中诱导凋亡，而PIK3CA突变细胞显示 对这种组合有抵抗力。要开始解密介导灵敏度的机制 SRC和MEK1/2抑制作用，我使用了> 400蛋白的反相蛋白阵列（RPPA）和 磷蛋白并将促凋亡蛋白BIM鉴定为反应的潜在介体。所以， 我的建议的目标是确定合作SRC和MAPK信号传导对凋亡的调节 在甲状腺癌中。具体而言，在AIM 1中，我将确定PI3K/AKT依赖性的调节和作用 在介导凋亡反应时的信号传导，在AIM 2中，我将确定凋亡的机制 由SRC和MAPK信号调节，最后在AIM 3中，我将确定合并的SRC和 MEK1/2对肿瘤生长，转移和体内凋亡诱导的抑制作用。这个建议 强调对介导对SRC和MEK1/2抑制反应的机制的分子理解 制定新的策略来增强这些效果和潜在的方法来使抗性肿瘤敏感。这 拟议研究的完成将有助于国家癌症研究所履行其支持的使命 基础科学的癌症研究和培训。