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ABT-199 based therapies to treat neuroblastoma

基于 ABT-199 的神经母细胞瘤疗法

基本信息

批准号：
9899951
负责人：
Anthony Charles Faber
金额：
$ 35.98万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899951
关键词：
Adult Animal Model Apoptosis Apoptotic Award BCL1 Oncogene BCL2 gene BCL2L11 gene Cause of Death Cell Line Cessation of life Childhood Clinical Trials Combined Modality Therapy Data Drug Screening Evaluation FDA approved Funding Future Genomics Goals Grant Hypersensitivity In Vitro Infant MDM2 gene MYCN gene Malignant Childhood Neoplasm Malignant Neoplasms Mediating Methods Molecular Neuroblastoma PMAIP1 gene Patients Pharmaceutical Preparations Pharmacogenomics Preclinical Testing Publishing Refractory Research Design Research Project Grants Safety TP53 gene Testing Treatment Protocols Work anticancer activity base cancer cell cancer therapy chemotherapy combat design drug efficacy experimental study high risk high-throughput drug screening improved outcome in vitro Model in vivo inhibitor/antagonist innovation leukemia mouse model neuroblastoma cell new therapeutic target novel novel drug class novel therapeutics pre-clinical preclinical efficacy preclinical safety research clinical testing standard of care targeted cancer therapy targeted treatment virtual

项目摘要

High-risk neuroblastoma accounts for the second most pediatric cancer deaths. Amplification of MYCN accounts for many of these cases, while other less-understood mechanisms account for non-MYCN amplified high-risk neuroblastoma. We have recently demonstrated that amplified MYCN is synthetic lethal to the FDA-approved BCL-2 inhibitor, venetoclax (ABT-199). Herein, we uncover several rational implementations of venetoclax in MYCN-amplified neuroblastoma therapy and aim to preclinically test them. In addition, we provide rational and evidence that venetoclax can be effective in combination in high-risk MYCN-wild-type neuroblastoma, based on a newly discovered apoptotic block in these cancers. Lastly, through high-throughput drug screening, we uncover a novel class of drug that has potent, specific and broad activity across neuroblastoma, and combines with venetoclax to eliminate virtually all neuroblastoma cells. Objectives: High-risk neuroblastoma is refractory to current treatment regimens. By studying the molecular vulnerabilities of these cancers, we propose several new promising treatments to specifically combat subsets of high-risk neuroblastoma, with the overall goal to ready these for clinical testing. Specific Aim #1. Determine anti-cancer activity of standard-of-care chemotherapy and venetoclax against molecularly heterogeneous neuroblastoma cell lines and animal models. Here, we will evaluate the efficacy of venetoclax with the standard-of-care chemotherapy in multiple mouse models of neuroblastoma. Specific Aim 2: Characterize the efficacy and safety of venetoclax/ MDM2 inhibitor combination therapy in p53 wild-type neuroblastoma in cell lines and animal models. Here, we will determine the mechanisms of in vitro efficacy of MDM2 inhibitors in combination with venetoclax in p53 wild-type neuroblastoma, and define vivo efficacy and safety. Specific Aim 3: Characterize the efficacy and safety of H3K27me3 inhibition alone and in combination with venetoclax. We have identified a novel class of drug with potent and specific activity in neuroblastoma. We will further define the mechanism(s) of this sensitivity in vitro and in vivo. Study Design/Methods: Utilizing an innovative pharmacogenomics approach that has uncovered several novel targeted therapies that have reached or are headed to clinical trials, we will evaluate other novel drugs for efficacy in neuroblastoma in combination with venetoclax. Using multiple in vitro models of neuroblastoma, we will study the relationship between particular drug vulnerabilities and the molecular underpinnings of that sensitivity. Lastly, we will rigorously evaluate preclinical efficacy and safety of our novel targeted therapy combinations in multiple and diverse animal models of neuroblastoma.

高风险神经母细胞瘤是导致儿童癌症死亡的第二大原因。其中许多案例都是 MYCN 的放大造成的，而其他不太了解的机制则是造成这种情况的原因。非 MYCN 扩增的高危神经母细胞瘤。我们最近证明，扩增的 MYCN 是对 FDA 批准的 BCL-2 抑制剂 Venetoclax (ABT-199) 具有合成致死作用。在此，我们揭晓几个 Venetoclax 在 MYCN 扩增神经母细胞瘤治疗中的合理实施并旨在进行临床前测试他们。此外，我们还提供了合理的证据证明 Venetoclax 联合用药在高危人群中可以有效。 MYCN-野生型神经母细胞瘤，基于这些癌症中新发现的细胞凋亡阻断。最后，通过高通量药物筛选，我们发现了一类新型药物，它具有有效、特异性和广泛性跨神经母细胞瘤的活性，并与维奈托克结合消除几乎所有神经母细胞瘤细胞。目的：高危神经母细胞瘤对当前的治疗方案难以治疗。通过研究分子针对这些癌症的脆弱性，我们提出了几种新的有前景的治疗方法来专门对抗这些癌症的子集高风险神经母细胞瘤的总体目标是为临床测试做好准备。具体目标#1。确定标准护理化疗和维奈托克的抗癌活性针对分子异质神经母细胞瘤细胞系和动物模型。在这里，我们将评估 Venetoclax 与标准护理化疗在多只小鼠中的疗效神经母细胞瘤模型。具体目标 2：表征 Venetoclax/MDM2 抑制剂联合疗法的有效性和安全性在细胞系和动物模型中的 p53 野生型神经母细胞瘤中。在这里，我们将确定 MDM2 抑制剂与 Venetoclax 联合使用的体外功效机制 p53 野生型神经母细胞瘤，并确定体内疗效和安全性。具体目标 3：表征单独和联合使用 H3K27me3 抑制的功效和安全性与维奈托克。我们已经发现了一类对神经母细胞瘤具有有效和特异性活性的新型药物。我们将进一步定义这种体外和体内敏感性的机制。研究设计/方法：利用创新的药物基因组学方法，发现了多种已经达到或即将进入临床试验的新型靶向疗法，我们将评估其他新药与维奈托克联合治疗神经母细胞瘤的疗效。使用神经母细胞瘤的多种体外模型，我们将研究特定药物的脆弱性与其分子基础之间的关系敏感性。最后，我们将严格评估我们的新型靶向治疗的临床前疗效和安全性多种不同神经母细胞瘤动物模型中的组合。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Venetoclax-based Rational Combinations are Effective in Models of MYCN-amplified Neuroblastoma.

DOI：
10.1158/1535-7163.mct-20-0710
发表时间：
2021-08
期刊：
MOLECULAR CANCER THERAPEUTICS
影响因子：
5.7
作者：
Dalton, Krista M.;Krytska, Kateryna;Lochmann, Timothy L.;Sano, Renata;Casey, Colleen;D'Aulerio, Alessia;Khan, Qasim A.;Crowther, Giovanna Stein;Coon, Colin;Cai, Jinyang;Jacob, Sheeba;Kurupi, Richard;Hu, Bin;Dozmorov, Mikhail;Greninger, Patricia;Souers, Andrew J.;Benes, Cyril H.;Mosse, Yael P.;Faber, Anthony C.
通讯作者：
Faber, Anthony C.