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-κB通路在癌症的发生和进展中显然很重要，但我们尚未完全了解该通路促进致癌表型的机制，并且临床上没有特异性抑制剂。最近的发现表明，典型和非典型的 NF-κB 都会导致癌症进展，从而提高了癌症相对于 NF-κB 的复杂性，但许多研究仅关注典型途径，然后得出结论：NF-κB 在特定癌症中很重要，但并非绝对关键。此外，结果表明 IKK 具有与其调节 NF-κB 能力无关的关键信号传导功能，这增加了复杂性；例如，我们发现 IKK 控制自噬和 mTORC1 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，我们和其他人确定了 IKK/NF-β 信号传导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-β 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-κB 信号传导对于 TIC 表型至关重要。在所有这些研究中，TIC 隔室中 NF-κB 活性增强/改变，尽管解释这一现象的机制尚不清楚。初步数据表明 PSA 低/AR 低和 PSA 高/AR 高前列腺癌细胞中存在不同的 IKK/NF-β 机制，并表明 IKKα 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 低的前列腺 TIC 对抗 AR 治疗有抵抗力，这表明前列腺癌的复发是由该细胞区室的存活/扩张驱动的。该提案的目标是：(i) 描述以下领域的独特贡献： 规范和非规范 NF-κB 对 Ras 驱动的癌症和乳腺癌的影响，(ii) 识别与癌症中规范和非规范 NF-κB 相关的转录输出，(iii) 确定 NF-κB 信号传导在驱动肿瘤起始细胞表型中的参与 - 重点关注脑癌、神经胶质瘤和前列腺癌，以及与 IKKα 通路参与相关的其他研究 促进 PSA-lo/AR-lo TIC 表型，假设这会驱动抗 AR 疗法的耐药性，(iv) 确定促进 TIC 中 NF-κB 反应改变的信号事件，(v) 表征 IKK 信号网络，将 IKK 信号传导与癌症中自噬和 mTORC1 信号传导的控制联系起来，假设 IKK 功能驱动这两种途径活跃， (vi) 确定 IKK 抑制剂的耐药机制 - 重点是通过剩余的 IKK/NF-κB 信号传导和激酶组重编程进行补偿，以及 (vii) 促进抑制剂进入临床前和临床环境。