权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mutant p53 as actionable cancer-specific target

突变 p53 作为可操作的癌症特异性靶点

基本信息

批准号：
10414801
负责人：
UTE Martha MOLL
金额：
$ 33.75万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
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：
2013-04-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10414801
关键词：
Ablation Acute Affect Alleles Amino Acids Biological Assay Cancer Patient Carcinoma Cell Death Cells Chemoresistance Chromatin Remodeling Factor Clinical Clustered Regularly Interspaced Short Palindromic Repeats DNA Binding DNA Binding Domain Data Death Rate Dependence Drug Targeting Epithelial Event Excision Exhibits Gene Activation Gene Transfer Genes Genetic Genetic Recombination Genetic Transcription Genomics Germ-Line Mutation Goals Grant Growth Heat-Shock Proteins 90 Human In Vitro KRASG12D Knock-in Knock-in Mouse Large Intestine Carcinoma Lead Lymphoma Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Mediating Metabolism Missense Mutation Modeling Molecular Molecular Conformation Mus Mutation Nature Neoplasm Metastasis Oncogenic Pancreatic Ductal Adenocarcinoma Pancreatic carcinoma Pathway interactions Patients Persons Pharmacology Phenotype Pre-Clinical Model Primary carcinoma of the liver cells Proteins Proteome Solid Neoplasm TP53 gene Testing The Cancer Genome Atlas Therapeutic Tissues Translating Transposase Tumor Suppressor Proteins cancer cell chaperone machinery cytotoxicity fitness gain of function gene repression genome-wide in vivo inhibitor insight liver cancer model mortality mouse model mutant neoplastic cell new therapeutic target pre-clinical programs recruit therapeutic target time use transcription factor transcriptome sequencing transcriptomics tumor tumor growth tumor progression ubiquitin-protein ligase

项目摘要

Project Summary The vast majority of p53 mutations are missense mutations in the DNA-binding domain (termed ‘mutp53’) that generate conformationally aberrant proteins with broadly abrogated functions. Importantly, in the previous grant cycle we generated new mouse models that definitively proved that certain hotspot missense mutant p53 proteins not only lose their tumor suppressor function, but acquire broad oncogenic gain-of-function (GOF) activities (‘mutp53GOF’). Our humanized p53R248Q knockin mice (termed ’Q’ mice) provided the long-sought compelling phenotype of faster onset of all spontaneously arising tumor types and significantly shorter survival compared to p53null littermates. Importantly, our finding translates to human cancers. In Li-Fraumeni patients harboring p53 germline mutations, the Q allele dramatically accelerates tumor onset by 10.5 years and leads to increased mortality compared to p53null-like Li-Fraumeni patients. Moreover, accumulating evidence from TCGA data suggests that sporadic cancer patients harboring specific GOF alleles have higher death rates than patients with p53 mutations that are functionally null. GOF contributes to malignant progression with increased proliferation, invasion, metastasis, chemoresistance, stroma remodeling and reprogrammed metabolism. A central feature of GOF is that mutp53 proteins exhibit massive constitutive stabilization, and that stabilization is the prerequisite for exerting GOF. We identified the HSP90 chaperone machinery, which protects mutp53 from its E3 ubiquitin ligases, as a major determinant of stabilization in vivo. Globally about 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 p53null tumors, which historically was the premier preclinical model used. Notably, we established that autochthonous mutp53GOF cancers develop a strong dependency on continued expression of high levels of mutp53 for tumor growth, maintenance and metastasis. Consequently, acute genetic (via floxQ) or pharmacologic (via Hsp90 inhibitors) ablation of mutp53 triggers strong tumor cytotoxicity in two distinct GOF mice, translating to major gains in survival by up to 59%, even in the absence of wildtype p53. These paradigm-shifting results identify mutp53 as an actionable cancer-specific drug target. Aim 1 So far we demonstrated GOF resulting in mutp53 tumor dependency - and its therapeutic exploitability - in the context of lymphoma and colorectal carcinoma. We will evaluate the therapeutic potential of targeting mutp53 in other major tumor types, specifically in epithelial-derived models of liver and pancreatic carcinomas. Aim 2 will determine the in vivo core network of pathways and interaction partners mediating mutp53GOF. We will use ChIPseq/RNAseq and functional proteome analyses to directly observe the dynamic events that occur upon p53 mutation during transformation in primary mutp53GOF-driven lymphoma. Aim 3 will use genome-wide transcriptional perturbation via CRISPR-mediated gene repression and activation to identify critical genetic sensitizers as novel therapeutic targets specific for mutp53GOF cancer cells.

项目总结

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Suppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity.

DOI：
10.1038/s41467-021-24064-1
发表时间：
2021-06-29
期刊：
Nature communications
影响因子：
16.6
作者：
Isermann T;Şener ÖÇ;Stender A;Klemke L;Winkler N;Neesse A;Li J;Wegwitz F;Moll UM;Schulz-Heddergott R
通讯作者：
Schulz-Heddergott R

The Gain-of-Function p53 R248W Mutant Promotes Migration by STAT3 Deregulation in Human Pancreatic Cancer Cells.

DOI：
10.3389/fonc.2021.642603
发表时间：
2021
期刊：
Frontiers in oncology
影响因子：
4.7
作者：
Klemke L;Fehlau CF;Winkler N;Toboll F;Singh SK;Moll UM;Schulz-Heddergott R
通讯作者：
Schulz-Heddergott R

Therapeutic Ablation of Gain-of-Function Mutant p53 in Colorectal Cancer Inhibits Stat3-Mediated Tumor Growth and Invasion.

DOI：
10.1016/j.ccell.2018.07.004
发表时间：
2018-08-13
期刊：
Cancer cell
影响因子：
50.3
作者：
Schulz-Heddergott R;Stark N;Edmunds SJ;Li J;Conradi LC;Bohnenberger H;Ceteci F;Greten FR;Dobbelstein M;Moll UM
通讯作者：
Moll UM

HER2/ErbB2 activates HSF1 and thereby controls HSP90 clients including MIF in HER2-overexpressing breast cancer.