Targeting stabilized mutant p53 protein

靶向稳定突变 p53 蛋白

• 批准号: 9038330
• 负责人: UTE Martha MOLL
• 金额: $ 35.65万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038330
• 关键词: Ablation; Acute; Alleles; Apoptosis; Attention; Breast Cancer Patient; Cancer Patient; Carcinoma; Cell Survival; Cells; Chemicals; Clinical; Clinical Trials; Complex; DNA Binding Domain; Dependency; Drug Targeting; Drug effect disorder; Etiology; Excision; Exhibits; Genetic; Goals; HDAC6 gene; HSPB1 gene; Health; Heat-Shock Proteins 90; Human; Knock-in; Knock-in Mouse; Knockout Mice; Lead; Life; Link; LoxP-flanked allele; Lymphoma; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Missense Mutation; Modeling; Molecular Chaperones; Mus; Mutation; Neoplasm Metastasis; Normal tissue morphology; Oncogenes; Oncogenic; Patients; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Protein p53; Proteins; Resistance; SCID Mice; Sampling; Series; Skin Carcinogenesis; Squamous cell carcinoma; Staging; System; TP53 gene; Testing; Therapeutic; Transplantation; Tumor Suppressor Proteins; Vorinostat; Withdrawal; Xenograft procedure; antitumor effect; base; cancer cell; chaperone machinery; cytotoxicity; gain of function; in vivo; inhibitor/antagonist; killings; knock-down; mouse model; mutant; next generation; novel; novel strategies; predictive marker; prevent; prospective; research study; response; sarcoma; small molecule inhibitor; treatment response; tumor; tumorigenesis; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): The vast majority of p53 mutations are missense mutations in the DNA-binding domain (mutp53) that generate conformationally aberrant proteins with broadly abrogated functions. Importantly, missense mutp53 proteins not only lose their tumor suppressor function, but often acquire oncogenic gain-of-function (GOF) to drive tumorigenesis. GOF contributes to malignant progression with higher proliferation, invasion, metastatic ability and chemoresistance. A central feature of GOF is that nearly all mutp53 proteins exhibit massive constitutive stabilization, and that stabilization is the prerequisite for exerting GOF. Currently, ~ 11 million people are living with tumors expressing highly stabilized mutp53. Importantly, our findings indicate that the oncogenic 'wiring' of mutp53 tumors fundamentally differs from p53-null tumors, historically the premier preclinical model used. We find that mutp53 cancers have developed a strong dependency on high levels of mutp53 for survival. Thus, its acute withdrawal triggers strong spontaneous cytotoxicity in xenografts. We identified that the heat shock protein 90 chaperone (HSP90) is a major determinant of mutp53 stabilization. This identifies acute depletion of mutp53 as a very promising clinical strategy, and a potentially rather rapidly attainable goal in p53-based therapy. HSP90 is highly upregulated specifically in cancers but not in normal tissues. Importantly, the HSP90 machinery is a crucial facilitator of cancer cell survival by supporting proper folding of conformationally aberrant oncogenes including mutp53. Mechanistically, HSP90 protects mutp53 via stable complex ('caging') from its E3 ligases. Thus, goals of this project are to determine whether established tumors require continued expression of stabilized mutp53 for their maintenance in vivo, and to explore whether destabilizing mutp53 - by attacking the chaperone support on which they depend - is a promising new mutp53-specific anticancer strategy. This is an immensely important unsolved problem that is understudied and urgently needs more attention, with a high translational potential to achieve true clinical impact. Aim 1 determines if continued expression of high levels of mutant p53 is essential for maintenance of established tumors in vivo. We will perform genetic proof-of-principle experiments using acute ablation in mice. To this end, we generated a novel humanized inactivatable mutp53 KI model and will test it in a spontaneous and induced cancer context in vivo. Aim 2 asks whether small molecule inhibitors of the HSP90-HDAC6 chaperone have a preferential therapeutic response in mutp53 cancer cells in vivo. This will be extensively tested in xenografts and two different hotspot mutp53 KI mouse models. We will also test if mutp53 is a predictive biomarker for response to HSP90i-based therapy in three retrospective/ prospective clinical trials of lung and breast cancer patients. Also, causality studies on mechanism of drug action will be performed. Aim 3 is based on a novel unsuspected link between aberrant mutp53 stabilization and the tumor-associated HSP27 chaperone system that we uncovered. We will test if the HSP27 chaperone is a mechanistically independent second determinant of mutp53 stabilization.

描述（由申请人提供）：绝大多数p53突变是dna结合域（mutp53）的错义突变，产生具有广泛废除功能的构象异常蛋白。重要的是，错义mutp53蛋白不仅失去其肿瘤抑制功能，而且经常获得致癌功能获得（GOF）来驱动肿瘤发生。GOF具有更高的增殖、侵袭、转移能力和化疗耐药性，有助于恶性进展。GOF的一个核心特征是几乎所有的mutp53蛋白都表现出大量的组成稳定性，而这种稳定性是基因突变的先决条件