Anti-tumor potential of temperature-sensitive p53 mutants

温度敏感 p53 突变体的抗肿瘤潜力

基本信息

批准号：
10209252
负责人：
JIANDONG CHEN
金额：
$ 44.46万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10209252
关键词：
Apoptosis Binding Biological Assay Brain Bypass CRISPR/Cas technology Cancer Patient Categories Cell Cycle Cell Cycle Arrest Cell Death Clinical DNA Binding DNA Binding Domain DNA Sequence Databases Disease remission Drug Targeting Frequencies Genes Genetic Transcription Genetically Engineered Mouse Heart Arrest Human Immunocompetent Individual Libraries Lung Neoplasms Lymphoma MDM2 gene Malignant Neoplasms Modeling Molecular Mus Mutant Strains Mice Mutation Patients Pharmaceutical Preparations Pharmacology Point Mutation Procedures Refractory Relapse Solid Neoplasm Structural defect Surface System TP53 gene Temperature Testing Therapeutic Therapeutic Effect Therapeutic Uses Thermogenesis Treatment Efficacy Tumor Suppressor Proteins Variant Xenograft Model Xenograft procedure base cancer therapy chemotherapy clinical translation clinically relevant deep sequencing experimental study functional status improved in vivo induced hypothermia mouse model mutant natural hypothermia neglect neoplastic cell novel strategies pancreatic neoplasm patient derived xenograft model prevent response senescence standard of care targeted treatment temperature sensitive mutant tumor tumor xenograft

项目摘要

The p53 tumor suppressor is frequently inactivated by mutations in cancer. Most p53 point mutations are located in the DNA binding domain that prevent folding or disrupt the DNA binding surface. Rescuing the structural defect and transcriptional activity of mutant p53 in tumor cells should induce cell death or cell cycle arrest that bring significant therapeutic benefits. However, this hypothesis remains unproven because currently there are no specific drugs capable of efficiently reactivating mutant p53. To bypass this limitation and rigorously test the clinical potential of mutant p53 functional rescue, we established a procedure to induce sustained hypothermia in mice by pharmacological blockade of brain- regulated thermogenesis. This mouse model enabled us to use hypothermia to reactivate temperature- sensitive (ts) p53 mutants in tumors to evaluate therapeutic efficacy. Preliminary experiments demonstrated the ability of ts p53 activation in combination with chemotherapy to induce regression of lymphoma xenografts. Importantly, durable remission was observed in a subset of tumors. This promising finding provides proof-of-concept for mutant p53 functional rescue as a potential cancer treatment. Furthermore, since ~14% of p53 point mutants in cancer are temperature-sensitive, our results raised the possibility of using therapeutic hypothermia to treat tumors expressing ts mutant p53. To explore the translational potential and molecular mechanism of this novel approach, we propose the following specific aims: (1) Investigate tumor response to ts p53 activation and optimize therapeutic efficacy. (2) Investigate the potential of ts mutant p53 in solid tumors and PDX models. (3) Investigate the effect of endogenous ts p53 activation using a genetically engineered mouse model. (4) Identify all p53 ts mutants with tumor suppressor activity in vivo by saturation screen. These experiments will provide proof-of-concept for specific targeting of tumors expressing ts mutant p53, with the potential to impact a large number of cancer patients.

p53肿瘤抑制剂经常被癌症突变灭活。大多数P53点突变位于DNA结合结构域中，可防止折叠或破坏DNA结合表面。营救突变体p53在肿瘤细胞中的结构缺陷和转录活性应诱导细胞死亡或细胞周期停滞带来了可观的治疗益处。但是，这个假设仍然存在未经证实的，因为目前没有能够有效重新激活突变体p53的特定药物。到绕过此限制，并严格测试突变体p53功能救援的临床潜力，我们建立了一种通过药理学封锁脑的障碍，以诱导小鼠持续体温过低的程序 - 调节的热发生。该小鼠模型使我们能够使用体温过低来重新激活温度肿瘤中敏感（TS）p53突变体评估治疗功效。初步实验证明了TS p53激活与化学疗法结合诱导回归的能力淋巴瘤异种移植。重要的是，在肿瘤的一部分中观察到了持久的缓解。这有希望的发现为突变体p53功能救援提供了概念验证，作为潜在的癌症治疗。此外，由于癌症中约有14％的p53点突变体对温度敏感，所以结果增加了使用治疗性低温治疗表达TS突变体p53的肿瘤的可能性。为了探索这种新方法的翻译潜力和分子机制，我们提出了以下特定目的：（1）研究肿瘤对TS P53激活的反应并优化治疗功效。（2）研究TS突变体p53在实体瘤和PDX模型中的潜力。（3）使用基因工程小鼠研究内源性TS p53激活的效果模型。（4）通过饱和筛选在体内识别所有具有肿瘤抑制活性的P53 TS突变体。这些实验将为表达TS突变体的肿瘤的特定靶向提供概念验证 p53，有可能影响大量癌症患者。