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（由适用提供）：IKK/NF-B途径在癌症的开始和进展中显然很重要，但是我们不完全了解该途径促进致癌表型的机制，并且在诊所中没有特定的抑制剂。癌症相对于NF-B的复杂性是通过最近发现的，即规范和非规范的NF-B都会促进癌症的进展，但许多研究仅关注规范途径，然后包含NF-B在特定癌症中很重要，但绝对关键。另外，结果表明IKK具有关键信号传导功能与调节NF-B的能力分开，因此提高了复杂性。例如，我们发现IKK控制自噬和MTORC1信号传导，这在许多癌症中都很重要 - 但被认为是相互拮抗的。最近，我们和其他人在促进三阴性乳腺癌肿瘤启动（TIC）表型中确立了IKK/NF-B信号传导的作用，有证据表明规范和非基础IKK/NF-B都很重要。此外，前列腺癌和神经胶质瘤的初步数据表明，IKK/NF-B信号对于TIC表型至关重要。在所有这些研究中，尽管尚不清楚这是解释这一点的机制，但NF-B活性在TE TIC室中得到了增强/改变。初步数据表明，PSA-LOW/AR-LOW和PSA-HIGH/AR-HIGH/AR-HIGH前列腺癌细胞中的IKK/NF-B机制有分歧，表明IKK在促进前列腺TICS中的AR水平降低，可能通过直接磷酸化。 PSA-LOW/AR-LOW前列腺测试对抗AR疗法具有抗性，这表明前列腺癌的复发是由该细胞室的存活/扩张驱动的。该建议的目标是：（i）表征 （II）确定与癌症的规范和非规范NF-B相关的转录输出，（III）确定NF-B信号在推动肿瘤发射细胞表型中的参与确定与脑，脑，gli瘤相关的研究有关的研究，该研究与脑，gli瘤的研究相关，并涉及肿瘤的其他研究 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）确定对IKK抑制剂抗性的机制 - 通过剩余的IKK/NF-B信号传导以及Kinome重新编程和（VII）来促进抑制剂进入前临床和临床环境。