Targeting p53 conformational defects to arrest carcinogenesis

针对 p53 构象缺陷阻止癌变

基本信息

批准号：
10524144
负责人：
Alice Soragni
金额：
$ 9.01万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2022-07-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524144
关键词：
3-Dimensional Amyloid Antibodies Archives Automobile Driving Benign Biological Assay CCNE1 gene Cancer cell line Carcinoma Carcinoma in Situ Cell Death Cell Death Induction Cell Proliferation Cells Characteristics Clinical Defect Disease Disease Progression Distal Early Intervention Early treatment Epithelial Cells Event Future Gene Expression Profile Genes Heat-Shock Proteins 90 Human In Vitro Lesion MDM2 gene Malignant Neoplasms Malignant neoplasm of ovary Mammalian Oviducts Missense Mutation Modeling Molecular Molecular Conformation Mucous Membrane Mutation Normal tissue morphology Organoids Outcome Ovarian Serous Adenocarcinoma Patient Selection Patients Peptides Periodicity Phase Play Prevention therapy Proteins Reporting Resistance Role Sampling Serous Site Solubility Specimen Stratification Structural defect TP53 gene Testing Therapeutic Tube Work aggregation pathway cancer prevention cancer therapy carcinogenesis cellular engineering chemotherapy clinical development clinically relevant design in vivo in vivo Model inhibitor innovation mouse model mutant neoplastic ovarian cancer prevention ovarian neoplasm peptide drug premalignant preneoplastic cell prevent protein aggregation protein folding rational design tool tumor tumor progression

项目摘要

PROJECT SUMMARY p53 mutations are believed to arise at a very early stage in carcinogenesis (Leitao et al, 2004) and were reported in tubal intraepithelial carcinoma (TIC) which is a common early precursor lesion for high-grade serous carcinoma of the ovaries (Kindelberger et al, 2007). TIC and ovarian serous carcinoma from the same patient most frequently share the same p53 mutation (Kindelberger et al, 2007). Moveover, p53 mutations are also identified in pre-neoplastic subpopulations of cells in the benign fallopian tube mucosa, termed “p53 signature” (Lee et al, 2007). Both p53 signatures and TIC lesions are found in the distal end of the fallopian tube, which is considered as a possible site of origin for ovarian cancer (Lee et al, 2007; Kurman et al, 2010). p53 mutants have the capability to promote its aggregation, which is a mechanism of inactivating the protein. Here we will determine whether aggregation of newly acquired p53 mutations in pre-neoplastic and early lesions is a defined molecular event that favors cancer progression through p53 inactivation. Our first aim is to whether aggregation of mutant p53 is present in clinical samples of p53 signatures or TICs in archival ovarian cancer specimens. Results of this aim will determine whether p53 aggregation is a feature that can be used to discriminate pre-malignant tissue from normal tissue, and can be targeted for early therapy and prevention of ovarian cancer. We previously demonstrated that p53 aggregation is an actionable event, and developed a peptide drug, ReACp53, currently in clinical development as an anti-cancer therapy. Next, we will test the hypothesis that ReACp53 can be efficacious on preventing conversion of pre-malignant lesions to full blown ovarian cancer. ReACp53 is a cell-penetrating peptide that was rationally designed to arrest p53 aggregation and results in rescue of p53 function and induction of cell death in cancers bearing aggregated mutant p53. Here we will test whether early administration of ReACp53 can prevent progression of pre-malignant lesions to ovarian cancer. Lastly we will attempt to identify a gene expression signature for ovarian tumors that carry p53 aggregates and respond to ReACp53. This will enable the rapid identification of cases for which ReACp53 will be effective and will allow us to fully estimate the fraction of tumors that are likely to respond to this therapy.

项目概要 p53 突变被认为出现在癌症发生的非常早期阶段（Leitao 等，2004）并有报道输卵管上皮内癌 (TIC)，这是高级别浆液性癌常见的早期前驱病变卵巢浆液性癌 (Kindelberger et al, 2007)。经常共享相同的 p53 突变（Kindelberger 等，2007）。此外，还鉴定了 p53 突变。在良性输卵管粘膜的肿瘤前细胞亚群中，称为“p53 特征”（Lee 等人， 2007）p53 特征和 TIC 病变均发现于输卵管远端，这被认为是作为卵巢癌的可能起源位点（Lee 等人，2007；Kurman 等人，2010）。促进其聚集的能力，这是使蛋白质失活的机制。肿瘤前和早期病变中新获得的 p53 突变的聚集是否是一个明确的分子通过 p53 失活有利于癌症进展的事件。我们的首要目标是确定 p53 特征或 TIC 的临床样本中是否存在突变 p53 的聚集。该目标的结果将确定 p53 聚集是否是一个特征。可用于区分癌前组织与正常组织，并可作为早期治疗和治疗的目标预防卵巢癌。我们之前证明了p53聚集是一个可操作的事件，并开发了一种肽药物， ReACp53，目前正在作为一种抗癌疗法进行临床开发接下来，我们将检验以下假设： ReACp53 可有效防止癌前病变转变为全面的卵巢癌。 ReACp53 是一种细胞穿透肽，经过合理设计，可阻止 p53 聚集并导致在携带聚集突变体 p53 的癌症中挽救 p53 功能并诱导细胞死亡。早期施用 ReACp53 是否可以预防癌前病变进展为卵巢癌。最后，我们将尝试鉴定携带 p53 聚集体的卵巢肿瘤的基因表达特征，响应 ReACp53，这将能够快速识别 ReACp53 有效的病例，并且将使我们能够充分估计可能对该疗法产生反应的肿瘤比例。