Targeting the Chk1-Suppressed Apoptotic Pathway in HNSCC

靶向 HNSCC 中 Chk1 抑制的凋亡途径

• 批准号: 8558614
• 负责人: Samuel Sidi
• 金额: $ 35.69万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-05 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8558614
• 关键词: ATM Signaling Pathway; Acinus organ component; Antineoplastic Agents; Apoptosis; Apoptotic; Area; Ataxia-Telangiectasia-Mutated protein kinase; BCL2 gene; Biological Markers; Biology; Bypass; Caspase; Caspase Inhibitor; Cell Death; Cell Line; Cells; Cessation of life; Client; Clinical Trials Design; Complex; DNA Damage; DNA Fragmentation; Data; Death Domain; Defect; Deoxyribonucleases; Development; Diagnostic; Disease; Event; Foundations; Genetic; Genetic Determinism; Genotype; Goals; Head and Neck Squamous Cell Carcinoma; Heterogeneity; Human; Investigation; Knowledge; Literature; MDM2 gene; Maintenance; Malignant Epithelial Cell; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mitochondria; Modeling; Molecular; Mus; Mutation; NPM1 gene; Nuclear; Oncogenes; Pathway interactions; Patients; Peptide Hydrolases; Pharmacodynamics; Phenotype; Phosphoproteins; Phosphorylation; Process; Proteins; Publishing; Radiation; Radiation Tolerance; Radiation therapy; Radioresistance; Receptor Signaling; Recurrence; Research; Resistance; Role; Sampling; Signal Transduction; Survival Rate; TP53 gene; Testing; Therapeutic; Translating; Treatment Efficacy; Vertebral column; Vertebrates; Work; Zebrafish; base; cancer cell; cancer genomics; caspase-2; design; improved; in vivo; in vivo Model; inhibitor/antagonist; killings; metaplastic cell transformation; mortality; mutant; neoplastic cell; novel; overexpression; pre-clinical; public health relevance; receptor; research study; response; scaffold; tool; tumor

DESCRIPTION (provided by applicant): Defects in p53 signaling eliminate apoptotic responses to radiation therapy in many human cancers. In head and neck squamous cell carcinoma (HNSCC), the fifth most common cancer worldwide, TP53 mutations cause locoregional recurrence of radioresistant tumors, an invariably fatal form of the disease. Thus there is an urgent need for agents that will bypass mutant TP53 to restore radiosensitivity in HNSCC. This proposal focuses on an emerging apoptotic pathway, designated 'Chk1-suppressed' (CS) apoptosis, whose activation by Chk1 inhibitors restores radiosensitivity in p53-deficient zebrafish, mouse, and human cancer cells (Sidi et al., Cell 2008). We propose that Chk1 inhibitors and associated CS pathway define a promising therapeutic opportunity for TP53 mutant HNSCC. Our work has elucidated the core backbone of the CS pathway, which comprises a novel ATM/ATR-caspase-2 axis that bypasses p53 and attendant mitochondrial and death-receptor signaling cascades. Recently, we identified the PIDDosome (PIDD-RAIDD-caspase-2 complex), but not the intrinsic apoptosome or extrinsic DISC, as the caspase-activation platform at work in the CS pathway. These results strengthen the notion that the CS axis defines a third apoptotic pathway in vertebrate cells and were published in the September 14th issue of Molecular Cell (Ando et al. Mol Cell 2012). While we hypothesize that the CS pathway will be therapeutically effective in TP53 mutant HNSCC, the extreme heterogeneity of this disease makes it essential that we develop biologic tools that predict or assess PIDDosome activity in tumors. However, our molecular understanding of PIDDosome biology is very limited. To both deepen our understanding of PIDDosome signaling and identify predictive and pharmacodynamic biomarkers of CS pathway therapy, we propose three specific aims. The first and second aims are designed to identify novel PIDDosome regulators and substrates, respectively, by elucidating the roles of four PIDD-interacting molecules we recently identified. The third aim integrates cutting-edge cancer genomics with in vivo functional genetics in zebrafish to identify genetic predictors of HNSCC response to CS pathway therapy. Candidate predictive genotypes will be functionally characterized using the functional CS pathway markers identified in Aim 1, Aim 2, or our previous studies, and validated in ex vivo cultures of primary HNSCC samples from the OR. In summary, we aim to make a significant impact in the newly emerging area of PIDDosome-mediated apoptotic signaling, thereby translating CS apoptosis into an effective HNSCC therapy.

描述(由申请人提供)：在许多人类癌症中，p53信号的缺陷消除了对放射治疗的凋亡反应。在头颈部鳞状细胞癌(HNSCC)中，TP53基因突变会导致放射抵抗肿瘤的局部区域复发，这种肿瘤总是一种致命的疾病形式。因此，迫切需要能够绕过突变体TP53的药物来恢复HNSCC的放射敏感性。这项建议侧重于一种新出现的凋亡途径，称为“Chk1抑制的”(CS)凋亡，Chk1抑制剂激活该途径可恢复p53缺失的斑马鱼、小鼠和人类癌细胞的放射敏感性(Sidi等人，Cell 2008)。我们认为，Chk1抑制剂和相关的CS通路为TP53突变的HNSCC提供了一个有希望的治疗机会。我们的工作阐明了CS通路的核心骨架，它包括一个新的ATM/ATR-caspase-2轴，绕过P53以及伴随而来的线粒体和死亡受体信号级联。最近，我们发现PIDDosome(Pidd-Raidd-caspase-2复合体)，而不是内在的凋亡体或外在的盘，是CS通路中起作用的caspase激活平台。这些结果强化了CS轴在脊椎动物细胞中定义了第三条凋亡途径的概念，并发表在9月14日出版的《分子细胞》(Ando等人)上。Mol Cell 2012)。虽然我们假设CS通路对TP53突变的HNSCC具有治疗效果，但这种疾病的极端异质性使我们有必要开发预测或评估肿瘤中PIDDosome活性的生物工具。然而，我们对PIDDosome生物学的分子理解是非常有限的。为了加深我们对PIDDosome信号的理解，并确定CS途径治疗的预测性和药效学生物标志物，我们提出了三个具体目标。第一个和第二个目标是通过阐明我们最近发现的四个与PIDD相互作用的分子的作用，分别鉴定新的PIDDosome调节剂和底物。第三个目标是将前沿癌症基因组学与斑马鱼体内功能遗传学相结合，以确定HNSCC对CS途径治疗的反应的遗传预测因子。候选预测基因类型将使用AIM 1、AIM 2或我们之前的研究中确定的功能性CS途径标记进行功能表征，并在来自OR的原代HNSCC样本的体外培养中进行验证。总之，我们的目标是在PIDDosome介导的凋亡信号这一新兴领域产生重大影响，从而将CS细胞凋亡转化为有效的HNSCC治疗。