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Targeting the Chk1-Suppressed Apoptotic Pathway in HNSCC

靶向 HNSCC 中 Chk1 抑制的凋亡途径

基本信息

批准号：
8841596
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
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-05 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8841596
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 genetic predictors improved in vivo in vivo Model inhibitor/antagonist killings metaplastic cell transformation mortality mutant neoplastic cell novel overexpression pre-clinical public health relevance radiation response radioresistant receptor research study response scaffold tool tumor

项目摘要

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）：p53信号传导缺陷消除了许多人类癌症对放射治疗的凋亡反应。在头颈部鳞状细胞癌（HNSCC）中，TP 53突变导致放射抗性肿瘤的局部复发，这是该疾病的一种致命形式。因此，迫切需要将绕过突变体TP 53以恢复HNSCC中的放射敏感性的试剂。该提议集中于一种新出现的凋亡途径，称为“Chk 1抑制的”（CS）凋亡，其通过Chk 1抑制剂的激活恢复了p53缺陷型斑马鱼、小鼠和人癌细胞的放射敏感性（Sidi et al.，Cell 2008）。我们认为Chk 1抑制剂和相关的CS通路为TP 53突变型HNSCC定义了一个有希望的治疗机会。我们的工作已经阐明了CS通路的核心骨架，该通路包括一个新的ATM/ATR-caspase-2轴，该轴绕过p53和伴随的线粒体和死亡受体信号级联。最近，我们确定了PIDDosome（PIDD-RAIDD-caspase-2复合物），而不是内在的DISC或外在的DISC，作为在CS通路中起作用的caspase激活平台。这些结果加强了CS轴定义脊椎动物细胞中第三种凋亡途径的概念，并发表在9月14日出版的《分子细胞》（Ando et al. Mol Cell 2012）上。虽然我们假设CS途径在TP 53突变型HNSCC中治疗有效，但这种疾病的极端异质性使得我们开发预测或评估肿瘤中PIDDosome活性的生物工具至关重要。然而，我们对PIDDosome生物学的分子理解非常有限。为了加深我们对PIDDosome信号传导的理解并鉴定CS通路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。第一个和第二个目的是为了确定新的PIDDosome监管机构和底物，分别阐明了我们最近发现的四个PIDD相互作用分子的作用。第三个目标是将尖端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途径治疗反应的遗传预测因子。候选预测基因型将使用Aim 1、Aim 2或我们先前研究中鉴定的功能性CS途径标志物进行功能表征，并在来自OR的原代HNSCC样本的离体培养物中进行验证。总之，我们的目标是在PIDDosome介导的凋亡信号传导的新出现的领域产生重大影响，从而将CS凋亡转化为有效的HNSCC治疗。