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

基本信息

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
项目类别：
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

项目摘要

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：由于缺乏治疗手段，晚期甲状腺癌患者的预后仍然很差，生存率也很低。有效的疗法。虽然 MAPK 通路占甲状腺中出现的大部分突变针对该通路的癌症（BRAF、RAS、RET/PTC）在临床上取得了不同程度的成功。最近的批准 BRAF 抑制剂与 MEK1/2 抑制剂联合治疗未分化甲状腺癌患者 (ATC) 具有 BRAF V600E 突变是具有里程碑意义的，但是，这种组合仅在以下子集中有效 ATC患者，对BRAF突变型甲状腺乳头状癌（PTC）患者无效；突出显示有必要为对当前疗法没有反应的患者确定新的治疗策略。我们的实验室已发现 Src 作为甲状腺癌的临床相关靶点，并且我们已经证明 Src 两种结构独立的 Src 抑制剂达沙替尼和萨拉卡替尼的抑制作用，可抑制生长、侵袭、和转移。然而，与许多单药靶向治疗一样，单药 Src 的临床反应在实体瘤中的抑制作用有限，表明联合疗法是必要的。因此，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益处，从而支持确定可与 Src 共同抑制的靶点的基本原理。为此，我们的实验室已证明 Src 和 MEK1/2 的共同抑制可协同抑制生长、提高存活率，并诱导 BRAF 和 RAS 突变甲状腺癌细胞凋亡，而 PIK3CA 突变细胞对这种组合有抵抗力。开始破译介导敏感性的机制结合 Src 和 MEK1/2 抑制，我使用了超过 400 个蛋白质的反相蛋白质阵列 (RPPA)，磷蛋白并鉴定出促凋亡蛋白 BIM 作为潜在的反应介质。所以，我的提案的目标是通过 Src 和 MAPK 信号传导来确定细胞凋亡的调节在甲状腺癌中。具体来说，在目标 1 中，我将确定 PI3K/AKT 依赖性的调节和作用信号传导介导细胞凋亡反应，在目标 2 中，我将确定细胞凋亡的机制由 Src 和 MAPK 信号传导调节，最后在目标 3 中，我将确定组合的 Src 和 MAPK 的作用 MEK1/2 在体内抑制肿瘤生长、转移和诱导细胞凋亡。这个提议强调对 Src 和 MEK1/2 抑制反应介导机制的分子理解开发新策略来增强这些作用以及使耐药肿瘤敏感的潜在方法。这完成拟议的研究将有助于国家癌症研究所履行其支持的使命基础科学领域的癌症研究和培训。