IKK/NF-kappaB Signaling in Cancer: Therapy, Resistance, and Tumor Initiating Cells

癌症中的 IKK/NF-kappaB 信号传导：治疗、耐药性和肿瘤起始细胞

• 批准号: 8956007
• 负责人: ALBERT Sidney BALDWIN
• 金额: $ 84.83万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-03 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8956007
• 关键词: Address; Animals; Automobile Driving; Autophagocytosis; Brain; Cells; Clinic; Clinical; Data; Event; Financial compensation; Glioma; Goals; Malignant Neoplasms; Malignant neoplasm of prostate; Modeling; Movement; NF-kappa B; Neoplasm Metastasis; Oncogenic; Output; Pathway interactions; Patients; Phenotype; Phosphorylation; Prostate; Recurrence; Resistance; Role; Signal Transduction; Testing; Tumor-Derived; cancer initiation; cancer therapy; inhibitor/antagonist; malignant breast neoplasm; pre-clinical; prostate cancer cell; public health relevance; resistance mechanism; response; targeted treatment; traditional therapy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor progression

 DESCRIPTION (provided by applicant): The IKK/NF-B pathway is clearly important in cancer initiation and progression, yet we do not fully understand the mechanisms whereby this pathway promotes the oncogenic phenotype and there are no specific inhibitors in the clinic. Complexity in cancer relative to NF-B is raised by recent findings that both canonical and non- canonical NF-B contribute to cancer progression, yet many studies only focus on the canonical pathway and then conclude that NF-B is important in a particular cancer but not absolutely critical. Additionally, complexity is raised by results demonstrating that IKK has critical signaling functions separate from its ability to regulate NF-B; for example we have found that IKK controls autophagy and mTORC1 signaling, both important in many cancers - yet thought to be mutually antagonistic. Recently we and others have established a role for IKK/NF-B signaling in promoting the triple-negative breast cancer tumor initiating cell (TIC) phenotype, with evidence that both canonical and non-canonical IKK/NF-B are important. Additionally, preliminary data in prostate cancer and glioma shows that IKK/NF-B signaling is critical for the TIC phenotype. In all of these studies, NF-B activity is enhanced/ altered in te TIC compartment, although a mechanism to explain this is not known. Preliminary data indicate a divergent IKK/NF-B mechanism in PSA-low/AR-low and PSA-high/AR- high prostate cancer cells and indicates the involvement of IKK in promoting reduced AR levels in the prostate TICs, potentially by direct phosphorylation. The PSA-low/AR-low prostate TICs are resistant to anti-AR therapy, suggesting that recurrence of prostate cancer is driven by survival/expansion of this cell compartment. Goals of this proposal are to: (i) characterize distinct contributions of canonical and non-canonical NF-B on Ras-driven cancer and on breast cancer, (ii) identify transcriptional output related to canonical and non- canonical NF-B in cancer, (iii) determine the involvement of NF-B signaling in driving the tumor-initiating cell phenotype - focused on brain, glioma, and prostate cancer, with additional studies related the involvement of the IKKpathway in promoting the PSA-lo/AR-lo TIC phenotype with the hypothesis that this drives resistance to anti-AR therapies, (iv) determine signaling events that promote an altered NF-B response in TICs, (v) characterize the IKK signaling network, relating IKK signaling to control of autophagy and mTORC1 signaling in cancers, with the hypothesis that IKK functions drives both pathways to be active, (vi) determine mechanisms of resistance to IKK inhibitors - focused on compensation by remaining IKK/NF-B signaling, and by kinome reprogramming and (vii) to facilitate movement of inhibitors into pre-clinical and clinical settings.

 描述（申请人提供）：IKK/NF-κ B B通路在癌症的发生和发展中显然是重要的，但我们并不完全了解该通路促进致癌表型的机制，临床上也没有特异性抑制剂。最近的发现提高了癌症中与NF-κ B B相关的复杂性，即经典和非经典NF-κ B B都有助于癌症进展，然而许多研究仅关注经典途径，然后得出结论NF-κ B B在特定癌症中是重要的，但不是绝对关键的.此外，证明IKK具有与其调节NF-κ B B的能力分开的关键信号传导功能的结果增加了复杂性;例如，我们发现IKK控制自噬和mTORC 1信号传导，这两者在许多癌症中都很重要，但被认为是相互拮抗的。最近，我们和其他人已经确定了IKK/NF-κ B B信号在促进三阴性乳腺癌肿瘤起始细胞（TIC）表型中的作用，有证据表明经典和非经典IKK/NF-κ B B都很重要。此外，前列腺癌和神经胶质瘤的初步数据显示IKK/NF-κ B B信号传导对TIC表型至关重要.在所有这些研究中，NF-κ B B活性在TIC隔室中增强/改变，尽管解释这一现象的机制尚不清楚.初步数据表明，在PSA-低/AR-低和PSA-高/AR-高前列腺癌细胞中存在不同的IKK/NF-κ B B机制，并表明IKK κ B可能通过直接磷酸化参与促进前列腺TIC中AR水平降低。PSA-低/AR-低前列腺TIC对抗AR疗法具有抗性，表明前列腺癌的复发是由该细胞区室的存活/扩增驱动的。本提案的目标是：㈠确定 典型和非典型NF-κ B B对Ras驱动的癌症和乳腺癌的影响，（ii）鉴定癌症中与典型和非典型NF-κ B B相关的转录输出，（iii）确定NF-κ B B信号传导参与驱动肿瘤起始细胞表型-集中于脑、神经胶质瘤和前列腺癌，其他研究将IKK途径参与促进PSA-lo/AR-lo TIC表型与假设这会导致对抗AR疗法的耐药性相关，（iv）确定促进TIC中改变的NF-κ B B应答的信号传导事件，（v）表征IKK信号传导网络，将IKK信号传导与癌症中的自噬和mTORC 1信号传导的控制相关联，假设IKK功能驱动两种途径活化，（vi）确定对IKK抑制剂的抗性机制-集中于通过剩余IKK/NF-κ B B信号传导和通过激酶组重编程的补偿，和（vii）促进抑制剂进入临床前和临床环境。