Therapeutic Targeting of Casein Kinase-1-delta in Primary and Metastatic Breast Cancer

酪蛋白激酶-1-δ 在原发性和转移性乳腺癌中的治疗靶向

• 批准号: 9710619
• 负责人: John L. Cleveland
• 金额: $ 72.95万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-04 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9710619
• 关键词: Acute; Apoptosis; Basal Cell; Binding Proteins; Biochemical; Biological; Biological Assay; Blood; Bone neoplasms; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Prevention; Breast Oncology; Breast cancer metastasis; Cancer Cell Growth; Cell Survival; Cell model; Cells; Chronic; Clinic; Complement; Complex; Cues; DNA Damage; Data; Dependence; Disease; Distant; Dose; Drug Combinations; Drug Kinetics; Extravasation; Genetic; Genetic Transcription; Growth; Human; Immune Evasion; Impairment; Interstitial Collagenase; Lung; MMP2 gene; MMP9 gene; Malignant Neoplasms; Matrix Metalloproteinases; Mediating; Metastatic Neoplasm to the Lung; Metastatic breast cancer; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Organ; P-Glycoprotein; Pathway interactions; Patient-derived xenograft models of breast cancer; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Play; Process; Property; Protein Isoforms; Protein-Serine-Threonine Kinases; Proteins; Proteomics; Refractory; Reporter; Reporting; Research; Resistance; Role; Safety; Signal Transduction; Site; Stem Cell Factor; Structure; Testing; Therapeutic; Tissues; Treatment Failure; Tumorigenicity; analog; base; beta catenin; bone; cancer clinical trial; cancer stem cell; casein kinase I; chemotherapy; design; efficacy testing; epithelial to mesenchymal transition; fluorescence imaging; genetic approach; improved; in vivo; inhibitor/antagonist; lead candidate; loss of function mutation; lung metastatic; malignant breast neoplasm; metastatic process; migration; mouse model; mutant; nanomolar; neoplastic cell; novel; novel therapeutics; outcome forecast; overexpression; phosphoproteomics; prevent; programs; resistance mechanism; safety assessment; self-renewal; side effect; small molecule; small molecule inhibitor; synergism; targeted treatment; therapeutic target; transcription factor; transcriptome sequencing; treatment response; triple-negative invasive breast carcinoma; tumor; tumor progression

Our Multi-PI research team recently reported that the delta isoform of casein kinase-1 (CK1δ) is amplified and/or overexpressed in over a third of all breast cancers, and that CK1δ activation is especially manifest in refractory forms of breast cancer such as triple-negative breast cancer (TNBC) that lacks targeted therapies. Further, we established that silencing CK1δ, or inhibition of CK1δ kinase activity with our nanomolar potent, highly selective small molecule dual inhibitor of CK1δ and CK1ε, specifically compromises the growth, survival and invasion of breast cancer cells that overexpress CK1δ. Notably, CK1δ inhibition also provokes tumor regression of TNBC, including lung metastatic TNBC and basal-like PDX breast cancer models, and without any overt side effects. Finally, we demonstrated that CK1δ inhibition disables WNT/β-catenin signaling, a frequently activated yet heretofore undruggable pathway that is activated in a broad cast of human malignancies. Importantly, our new studies suggest roles for CK1δ in TNBC metastasis, where we have now shown that CK1δ signaling is necessary to sustain the expression of: (i) transcription factors that direct the epithelial to mesenchymal transition (EMT), including Zeb1 and Snail2; (ii) matrix metalloproteinases-1 (MMP1), MMP2 and MMP9 that control TNBC cell invasion; and (iii) the breast cancer stem cell (BCSC) factors Bmi1 and Sox9 that control self renewal. Finally, we have shown that our CK1δ inhibitors have synergy with select in-clinic DNA-damaging chemotherapies used to treat TNBC. Collectively, these data support the hypotheses that CK1δ is a driver of breast cancer metastases and that targeting CK1δ will block and improve treatment of metastatic triple negative breast cancer. Accordingly, in Aim1 we will use an iterative and rigorous research operating plan (ROP) to improve the pharmacokinetic (PK) properties of our dual CK1δ/CK1ε inhibitors, and will develop and test the efficacy of CK1δ-selective inhibitors, to deliver safety assessment candidates suitable for subsequent IND-enabling studies. This ROP includes tests of synergy of our inhibitors with in-clinic agents used to treat TNBC. Further, using genetic approaches and our CK1δ inhibitors, in Aim 2 we will test roles for CK1δ in each step of the metastatic cascade, including intravasation, extravasation, latency and/or establishment at the secondary site. Finally, in Aim 3, using phosphoproteomics, activity-based proteomic profiling, and RNA-seq we will identify and test the roles of downstream effectors of CK1δ in controlling TNBC metastasis, and the EMT, MMPs and BCSC targets of CK1δ signaling. These studies, and those in TNBC that we have generated that are resistant to our CK1δ/ε inhibitors, will define acute and chronic changes in components of the kinome that could be exploited for combination studies, to improve therapeutic response and block the emergence of resistance. We submit our research program will establish CK1δ as a vulnerability to target metastatic triple negative breast cancer, and that the small molecule CK1δ/ε or CK1δ inhibitors that we develop will have a major impact in the breast oncology clinic.

我们的多PI研究小组最近报道说，酪蛋白激酶-1（CK1Δ）的三角洲同工型是放大器 和/或在所有乳腺癌的三分之一以上过表达，而CK1δ激活尤其表现在 乳腺癌的难治形式，例如缺乏靶向疗法的三阴性乳腺癌（TNBC）。 此外，我们确定对CK1δ的沉默或对CK1δ激酶活性的抑制作用， CK1δ和CK1ε的高度选择性小分子双分子抑制剂，特异性损害了生长，存活率 和过表达CK1δ的乳腺癌细胞的侵袭。值得注意的是，CK1Δ抑制也会引起肿瘤 TNBC的回归，包括肺转移性TNBC和基本的PDX乳腺癌模型，没有 任何明显的副作用。最后，我们证明了CK1δ抑制会禁用Wnt/β-catenin信号传导A 经常被激活但迄今为止的不良途径，这种途径被激活 恶性肿瘤。重要的是，我们的新研究表明CK1δ在TNBC转移中的作用 表明CK1δ信号传导是维持：（i）指导转录因子的表达所必需的 上皮到间质转变（EMT），包括Zeb1和Snail2； （ii）基质金属蛋白酶1 （MMP1），控制TNBC细胞侵袭的MMP2和MMP9； （iii）乳腺癌干细胞（BCSC） 控制自我更新的因素BMI1和Sox9。最后，我们已经表明我们的CK1δ抑制剂具有协同作用 使用用于治疗TNBC的精选临床内DNA破坏化疗。总的来说，这些数据支持 假设CK1δ是乳腺癌转移的驱动力，靶向CK1δ将阻塞，并且 改善转移性三重阴性乳腺癌的处理。根据AIM1，我们将使用迭代 以及严格的研究工作计划（ROP），以提高双重的药代动力学（PK）特性 CK1Δ/CK1ε抑制剂，并将发展和测试CK1Δ选择性抑制剂的效率，以提供安全性 评估候选者适合随后的辅助研究。此ROP包括测试的协同作用 我们用临界药物用于治疗TNBC的抑制剂。此外，使用遗传方法和我们的CK1δ 抑制剂，在AIM 2中，我们将在转移级联的每个步骤中测试CK1δ的作用，包括侵入， 次要地点的奢侈，潜伏期和/或建立。最后，在AIM 3中，使用磷蛋白质组学， 基于活动的蛋白质组学分析和RNA-seq，我们将识别和测试下游效应的作用 CK1δ控制TNBC转移，以及CK1δ信号传导的EMT，MMP和BCSC靶标。这些 研究以及我们已经产生的对CK1Δ/ε抑制剂具有抗性的TNBC的研究将定义急性 以及可以探索组合研究的成分的慢性变化，以改善 治疗反应并阻止抗药性的出现。我们提交我们的研究计划将建立 CK1δ是靶向转移性三重阴性乳腺癌的脆弱性，小分子CK1Δ/ε 我们开发的CK1δ抑制剂将对乳腺癌诊所产生重大影响。