Targeting gain-of-function p53 and BCL-2 for small cell lung cancer treatment

靶向功能获得性 p53 和 BCL-2 用于小细胞肺癌治疗

基本信息

批准号：
10355807
负责人：
Hisashi Harada
金额：
$ 18.14万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10355807
关键词：
ASCL1 gene Amino Acids Apoptosis Apoptotic Attenuated BCL2 gene BCL2L11 gene Biological Markers CREBBP gene Cancer Center Cancer Patient Cancer cell line Cell Death Cell Line Cells Characteristics Chemoresistance Classification Clinic Clinical Clinical Trials Combination Drug Therapy Data Down-Regulation Drug Screening EP300 gene FDA approved Family Genetic Transcription Genomics Grant HSP 90 inhibition Heat-Shock Proteins 90 Hypersensitivity In Vitro Knock-in Mouse Malignant Neoplasms Malignant neoplasm of lung Medical center Missense Mutation Mitochondria Modeling Mus Mutation Neuroendocrine Carcinoma Neurosecretory Systems PIK3CA gene PTEN gene Patient-Focused Outcomes Pattern Pharmaceutical Preparations Phase Phase I/II Clinical Trial Platinum Proto-Oncogene Proteins c-myc Publishing RB1 gene Recording of previous events Refractory Relapse Resistance Safety Solid Neoplasm TP53 gene Testing Tobacco Translating Tumor Cell Line Tumor Suppressor Proteins Xenograft procedure anticancer activity base cancer subtypes cancer therapy design effective therapy efficacy testing gain of function histone acetyltransferase inhibitor innovation irinotecan lung small cell carcinoma mimetics mouse model mutant novel patient derived xenograft model patient stratification pre-clinical preclinical safety radiation resistance targeted treatment therapy development transcription factor treatment strategy

项目摘要

Project Summary/Abstract Through a unique genomics and drug screening platform with ~800 solid tumor cell lines, we have found a subset of SCLC cell lines are hypersensitive to venetoclax, an FDA-approved inhibitor of BCL-2. These sensitive SCLCs have invariably high BCL-2 expression. Based on this data, a phase I/II clinical trial with venetoclax in SCLC patients has been designed at VCU (NCT04543916). It has been recently proposed that SCLC can be classified in four subtypes based on the expression of key transcription factors: SCLC-A (ASCL1 positive), SCLC-N (NeuroD1 positive), SCLC-P (POU2F3 positive), and SCLC-Y (YAP1 positive). Among them, SCLC-A and SCLC-P, which make up almost 80% of SCLC, frequently express high levels of BCL-2. We noticed that BCL-2 high and venetoclax-sensitive cell lines that we examined all belong to SCLC-A. However, we found that a subset of SCLC-A and SCLC-P showed high BCL-2 expression but were venetoclax-resistant. In addition, most of these SCLC cell lines have TP53 missense mutations, which make a single amino acid change. These mutants not only lose wild-type p53 tumor suppressor functions, but also acquire novel cancer-promoting activities [gain-of- function (GOF)]. It has been shown that GOF p53 expression is associated with chemo- and radio-resistance in a variety of cancers. Furthermore, a recent study with GOF p53 knock-in mouse models of SCLC suggests gain- of-function activity can attenuate chemotherapeutic efficacy. Based on these observations, we hypothesize that GOF p53 confers venetoclax-resistance and that simultaneous inhibition of BCL-2 and GOF p53 induces synergistic anticancer activity in a subset of SCLC-A and SCLC-P. Our preliminary data support this hypothesis: (1) Down-regulation of GOF p53 increases the expression of a BH3-only pro-apoptotic BIM and sensitizes to venetoclax in SCLC-P cells; (2) targeting GOF p53 by the HSP90 inhibitor, ganetespib, increases BIM expression and sensitizes to venetoclax in SCLC-P and SCLC-A cells. Although currently there are many combination studies for venetoclax proposed, the concept of simultaneous targeting of BCL-2 and GOF p53 is innovative and the combination of venetoclax and HSP90 inhibitors would be promising approach for SCLC treatment. In this proposal, we will determine the mechanism of action of this combination in vitro and the efficacy of this combination in a subset of SCLC-A and SCLC-P subtypes using cell line xenograft and patient-derived xenograft (PDX) models. Aim 1 will determine the mechanisms of cell death induced by venetoclax and ganetespib combination in SCLC cell lines in vitro. Aim 2 will define the efficacy of venetoclax and ganetespib combination treatment in mouse models of SCLC. Since venetoclax is FDA-approved and HSP90 inhibitors are being investigated in clinical trials including SCLC, the successful completion of the proposed project will lead to developing clinical trials at VCU Massey Cancer Center and Holmes Hunter VA Medical Center.

项目概要/摘要通过拥有约 800 个实体瘤细胞系的独特基因组学和药物筛选平台，我们发现了一个子集的 SCLC 细胞系对 Venetoclax（FDA 批准的 BCL-2 抑制剂）过敏。这些敏感的 SCLC BCL-2 的表达始终较高。基于该数据，进行了 Venetoclax 治疗 SCLC 的 I/II 期临床试验患者是在 VCU 设计的 (NCT04543916)。最近有人提出 SCLC 可分类根据关键转录因子的表达分为四种亚型：SCLC-A（ASCL1 阳性）、SCLC-N （NeuroD1 阳性）、SCLC-P（POU2F3 阳性）和 SCLC-Y（YAP1 阳性）。其中，SCLC-A和 SCLC-P 几乎占 SCLC 的 80%，经常表达高水平的 BCL-2。我们注意到 BCL-2 我们检查的高和venetoclax敏感细胞系均属于SCLC-A。然而，我们发现有一个子集 SCLC-A 和 SCLC-P 的 BCL-2 表达较高，但具有 Venetoclax 耐药性。此外，这些大多数 SCLC 细胞系存在 TP53 错义突变，导致单个氨基酸发生变化。这些突变体不不仅失去了野生型 p53 肿瘤抑制功能，而且还获得了新的促癌活性 [gain-of- 功能（GOF）]。研究表明，GOF p53 表达与化疗和放射抗性相关各种癌症。此外，最近一项针对 GOF p53 敲入 SCLC 小鼠模型的研究表明，功能丧失的活性会减弱化疗效果。根据这些观察，我们假设 GOF p53 赋予 Venetoclax 耐药性，同时抑制 BCL-2 和 GOF p53 会诱导 SCLC-A 和 SCLC-P 的子集具有协同抗癌活性。我们的初步数据支持这一假设： (1) GOF p53 的下调增加了仅 BH3 促凋亡 BIM 的表达并对 SCLC-P 细胞中的维奈托克； (2) HSP90 抑制剂 ganetespib 靶向 GOF p53，增加 BIM 表达并在 SCLC-P 和 SCLC-A 细胞中对 Venetoclax 敏感。虽然目前有很多组合 Venetoclax 研究提出，同时靶向 BCL-2 和 GOF p53 的概念具有创新性 Venetoclax 和 HSP90 抑制剂的组合将是 SCLC 治疗的有前途的方法。在这个建议，我们将确定该组合的体外作用机制以及该组合的功效使用细胞系异种移植物和患者来源的异种移植物组合 SCLC-A 和 SCLC-P 亚型的子集 (PDX) 模型。目标 1 将确定 Venetoclax 和 Ganetespib 诱导的细胞死亡机制体外 SCLC 细胞系中的组合。目标 2 将确定 Venetoclax 和 Ganetespib 组合的功效 SCLC 小鼠模型的治疗。由于 Venetoclax 已获得 FDA 批准，并且 HSP90 抑制剂正在开发中在包括 SCLC 在内的临床试验中进行了研究，拟议项目的成功完成将导致在 VCU Massey 癌症中心和 Holmes Hunter VA 医疗中心开展临床试验。