Targeting polo-like kinase for therapy of small cell lung cancer

靶向 Polo 样激酶治疗小细胞肺癌

基本信息

批准号：
10672386
负责人：
Taofeek K Owonikoko
金额：
$ 61.79万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672386
关键词：
Animal Model Apoptotic Applications Grants Artificial Intelligence Bayesian Method Biological Biological Markers Cancer Patient Cancer cell line Cell Line Characteristics Clinical Trials Clinical Trials Design Collecting Cell DNA sequencing Data Dependence Development Disease Drug Targeting Enzyme Inhibitor Drugs Frustration Gene Expression Gene Mutation Genetic Genetic Transcription Genomics Genotype Health Immunotherapy In Vitro MYC gene Machine Learning Malignant Neoplasms Metabolic Modeling Molecular Mutation Neoplasm Circulating Cells Newly Diagnosed Non-Small-Cell Lung Carcinoma Oncogenes Outcome PLK1 gene Pathway interactions Patients Performance Phase Phase II Clinical Trials Pre-Clinical Model Prognosis RB1 gene Recurrent disease Relapse Reproducibility Resistance Sampling TP53 gene Testing Therapeutic Tissue Sample Treatment Efficacy Tumor Suppressor Genes Xenograft Model Xenograft procedure anti-PD-1 anti-cancer biomarker validation chemotherapy clinical efficacy co-clinical trial cytotoxicity drug development effective therapy efficacy evaluation genomic data genomic profiles immune checkpoint blockade improved in vitro activity in vivo inhibitor innovation insight machine learning algorithm mouse model mutant novel novel drug combination novel strategies novel therapeutic intervention novel therapeutics overexpression participant enrollment patient biomarkers patient derived xenograft model pre-clinical pre-clinical assessment preclinical efficacy predictive marker programmed cell death ligand 1 protein expression resistance mechanism screening small cell lung carcinoma targeted agent targeted treatment transcriptome sequencing treatment optimization tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Small cell lung cancer (SCLC) is a significant health problem projected to afflict more than 35,000 new patients in the US in 2021. Less than 20% of newly diagnosed patients survive beyond 2 years. New and effective treatments are urgently needed to improve the poor outcome associated with this disease. SCLC is one of the most genomically unstable tumors but genomic-informed targeted therapy is currently not an established strategy in this disease. This is in part because most of the alterations in SCLC involve tumor suppressor genes such as TP53 and RB1, which cannot be targeted directly. We contend that while tumor suppressor gene alterations are not ideal targets for drug development efforts, the biological vulnerability conferred by these alterations can be exploited for therapeutic gains in SCLC. We employed an unbiased and agnostic preclinical screening to test several classes of targeted agents in a panel of SCLC cell lines. We discovered exquisite in vitro activity of four different polo like kinase 1 (PLK1) enzyme inhibitors, rigosertib, volasertib, CYC140 and Onvansertib. We subsequently confirmed the in vivo efficacy using traditional xenograft and patient-derived xenograft models of SCLC. We made the intriguing observation that SCLC cell lines harboring inactivating TP53 gene mutations are more sensitive to PLK1 inhibitors. We replicated this interesting observation using genetic depletion of wild type TP53 and overexpression of active mutant form of p53. These data therefore suggest that specific types of TP53 mutation could serve as potential predictive biomarkers to guide the development of PLK1 inhibitor as therapy of SCLC. We propose to test the hypotheses that (i.) Onvansertib, a potent PLK1 inhibitor, will have significant anticancer efficacy in relapsed SCLC patients and (ii.) Disruptive, inactivating TP53 gene mutation will predict efficacy of PLK1 inhibitors in patients. Also, that YAP1 positive subtype of SCLC will be vulnerable to PLK1 inhibitors alone and the combination with immune checkpoint blockade will further enhance efficacy in this subset of SCLC. We will pursue three innovative, independent but integrated specific aims: Aim 1: Conduct a phase II co-clinical trial to systematically assess the efficacy of onvansertib in patients with relapsed SCLC. A 2-stage phase II clinical trial will evaluate the efficacy of onvansertib in relapsed SCLC patients. Aim 2: Interrogate putative predictive biomarkers and elucidate whether and how inactivating TP53 gene mutations confer vulnerability to PLK1 inhibitors in SCLC. Preclinical efficacy of PLK1 inhibitors will be assessed in a large panel of genomically characterized SCLC cell lines. Activity will be correlated with specific types of TP53 mutations and with other biologically relevant genetic alterations in SCLC. Aim 3: Characterize mechanism(s) of acquired resistance to PLK1 inhibitor in SCLC and combination strategies to overcome resistance and enhance efficacy. Using lab and patient-derived preclinical models from the co-clinical trial, we will use machine learning and Artificial Intelligence approaches to interrogate putative resistance mechanisms and identify other strategies to enhance efficacy.

项目概要/摘要小细胞肺癌 (SCLC) 是一个严重的健康问题，预计将影响超过 35,000 名新患者到 2021 年，美国新诊断的患者中只有不到 20% 的患者能够存活超过 2 年。新颖有效迫切需要治疗来改善与这种疾病相关的不良结果。 SCLC 是其中之一大多数基因组不稳定的肿瘤，但目前尚未建立基于基因组的靶向治疗针对这种疾病的策略。这部分是因为 SCLC 的大部分改变都涉及肿瘤抑制因子 TP53和RB1等基因无法直接靶向。我们认为，虽然肿瘤抑制基因改变并不是药物开发工作的理想目标，基因改变所带来的生物脆弱性这些改变可用于 SCLC 的治疗效果。我们雇佣了一个公正且不可知论的人临床前筛选，在一组 SCLC 细胞系中测试几类靶向药物。我们发现四种不同的 polo 样激酶 1 (PLK1) 酶抑制剂 rigosertib、volasertib、 CYC140 和 Onvansertib。我们随后使用传统的异种移植和患者来源的 SCLC 异种移植模型。我们做了一个有趣的观察，即 SCLC 细胞系含有 TP53 基因失活突变对 PLK1 抑制剂更敏感。我们复制了这个有趣的使用野生型 TP53 的基因缺失和 p53 活性突变体的过度表达进行观察。这些因此，数据表明特定类型的 TP53 突变可以作为潜在的预测生物标志物指导 PLK1 抑制剂治疗 SCLC 的开发。我们建议检验以下假设：(i.) Onvansertib 是一种有效的 PLK1 抑制剂，对复发性 SCLC 患者具有显着的抗癌功效， (ii.) 破坏性、失活的 TP53 基因突变将预测 PLK1 抑制剂对患者的疗效。还有，那个 YAP1 阳性 SCLC 亚型对单独使用 PLK1 抑制剂以及与免疫疗法联合使用很敏感检查点封锁将进一步增强该小细胞肺癌亚型的疗效。我们将追求三个创新，独立但综合的具体目标：目标 1：进行 II 期联合临床试验以系统评估 onvansertib 对复发性 SCLC 患者的疗效。 2阶段II期临床试验将评估 onvansertib 对复发性 SCLC 患者的疗效。目标 2：询问假定的预测生物标志物并阐明 TP53 基因突变失活是否以及如何导致 SCLC 中对 PLK1 抑制剂的易感性。 PLK1 抑制剂的临床前疗效将在大量基因组特征 SCLC 细胞中进行评估线。活性将与特定类型的 TP53 突变以及其他生物学相关的 SCLC 的基因改变。目标 3：表征 PLK1 抑制剂获得性耐药的机制 SCLC 和克服耐药性并提高疗效的联合策略。使用实验室和患者来源的来自联合临床试验的临床前模型，我们将使用机器学习和人工智能方法询问假定的耐药机制并确定其他增强疗效的策略。