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Vulnerability of SCLC based on bi-allelic genetic inactivation of RB1 and TP53

基于 RB1 和 TP53 双等位基因失活的 SCLC 脆弱性

基本信息

批准号：
10371066
负责人：
EDWARD L SCHWARTZ
金额：
$ 8.31万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
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：
2019-04-12 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10371066
关键词：
Affect Alleles Apoptosis Apoptotic Binding Biological Markers CDKN1B gene CRISPR/Cas technology Cancer Patient Cell Cycle Regulation Cessation of life Chemoresistance Cisplatin Clinical Clinical Treatment Clinical Trials Combined Modality Therapy Congresses Data Disease Drug Combinations Drug Targeting Drug resistance Drug usage Etoposide Gene Mutation Genetic Goals Grant Growth Human In Vitro Knock-in Mouse Lead Malignant Neoplasms Mediating Metastatic Neoplasm to the Liver Missense Mutation Modeling Molecular Target Mus Mutation Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Oncogenic Organoids Outcome Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Play Proteins RB1 gene Regulation Research Retinoblastoma Retinoblastoma Protein Role Solid Neoplasm Specimen Survival Rate System TP53 gene Testing The Cancer Genome Atlas Therapeutic Agents Therapeutic Effect Toxic effect Tumor Suppressor Proteins Ubiquitination Xenograft procedure antitumor effect base cancer survival chemotherapy clinical predictors clinically relevant effective therapy gain of function mutation genome sequencing human model in vivo Model inhibitor lung cancer cell lung small cell carcinoma mouse model mutant novel novel therapeutics patient derived xenograft model phase III trial pre-clinical relapse patients response small molecule targeted treatment treatment strategy tumor tumorigenesis tumorigenic ubiquitin-protein ligase whole genome

项目摘要

There is an urgent need to identify new and effective drugs for small cell lung cancer (SCLC), a tumor characterized by aggressive growth, early metastases, and a 5-year survival rate of less than 2%. While it is initially chemosensitive, with 70% response rates to first-line therapy of cisplatin plus etoposide, most patients relapse after initial therapy with drug-resistant tumors. Dozens of new drugs have been tested for activity in SCLC over the decades, including more than 40 agents that have failed in phase III trials. None of the targeted drugs used in non-small cell lung cancer or other solid tumors are effective in SCLC. An outstanding feature of SCLC is the near uniform bi-allelic genetic inactivation of RB1 and TP53. However, since genetically inactivated RB1 and TP53 cannot be reactivated nor is it clinically feasible to reintroduce them into SCLC cells, this defining genetic feature has not led to treatment strategies for SCLC. In this grant, we will test the hypothesis that inhibiting a downstream target of Rb1 can re-establish the tumor suppressor and pro-apoptotic actions that were lost when Rb1 was inactivated. In preliminary studies, we found that modulation of only one downstream target of Rb1, the E3 ubiquitin ligase SCFSkp2/Cks1 (Skp2), can dramatically block the pro-tumorigenic consequences of the loss of Rb1, and induce Rb1-Skp2 synthetic lethal apoptosis in SCLC. This is due to the role Rb1 and Skp2 play in the regulation of p27 (CDKN1B), whereby the loss of Rb1 leads to the Skp2-mediated ubiquitination and degradation of p27 and the subsequent loss of cell cycle regulation. Most critically, we have identified active, small molecule Skp2 inhibitors to specifically target this vulnerability. The specific aims are: 1) To determine the role of the Cks1-Skp2 interaction in Rb1 and p53 deletion- induced SCLC. If the role is found to be essential, we will have identified another target to inhibit Skp2-medited p27 ubiquitination. Since some human SCLCs with p53 missense mutations may have gained new oncogenic functions (GOF), in addition to the loss of classic p53 functions, we will determine if these p53 GOF mutations affects the sensitivity to Skp2 inhibition. 2) To determine effects of Skp2 inactivation using genetic and pharmacologic approaches. Four different small molecule Skp2 inhibitors, with distinct molecular targets, will be used in several novel in vitro and in vivo models. Particular focus will be on SCLC liver metastasis, and on comparisons between chemotherapy-naïve and chemo-resistant SCLC cells. 3) To determine the antitumor effects of Skp2 inhibitors in a more clinically relevant mouse tumor model using a large panel of SCLC PDXs (patient-derived xenografts). Comparisons will be made between PDXs derived from chemotherapy-naïve and chemo-resistant SCLC tumors, including “isogenic” PDXs derived from serial specimens from the same patient pre- and post-chemotherapy. When completed, research in this proposal will potentially benefit most SCLC patients since bi-allelic inactivation of RB1 and TP53 is nearly uniform in SCLC.

小细胞肺癌（SCLC）是一种肿瘤，迫切需要寻找新的有效药物