权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Project 1: Targeting HSPA Proteins in Advanced and Recurrent Endometrial Cancer Therapy

项目 1：针对晚期和复发性子宫内膜癌治疗中的 HSPA 蛋白

基本信息

批准号：
10711636
负责人：
DORIS Mangiaracina BENBROOK
金额：
$ 40.34万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-23 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10711636
关键词：
Address Advanced Malignant Neoplasm Aneuploid Cells Animal Model Apoptosis Autophagocytosis Binding CDK4 gene Cancer Patient Cancer cell line Carcinoma Categories Cell Cycle Arrest Cell Cycle Progression Cell Death Cell Line Cell Nucleus Cell Survival Cells Centrosome Cessation of life Chromosomes Classification Client Clinical Trials Complement Complex Cyclin D1 Cyclin-Dependent Kinases DNA Sequence Alteration Data Defect Development Disease Dose Drug Combinations Drug Kinetics Endometrial Endometrial Carcinoma Endoplasmic Reticulum Epigenetic Process Epithelial Cells Future G1 Arrest GRP78 gene Gene Mutation Genes Genetic Genetic Induction Grant Growth Growth and Development function Heat shock proteins Homeostasis Incidence Induction of Apoptosis Malignant Female Reproductive System Neoplasm Malignant Neoplasms Measures Mediating Metabolism Mitochondria Molecular Molecular Chaperones Molecular Profiling Mutation Oncoproteins Organelles Organoids Outcome Outcomes Research PTEN gene Paclitaxel Patients Pharmaceutical Preparations Pharmacodynamics Phase Phase I Clinical Trials Phase Ib/II Clinical Trial Phosphorylation Phosphotransferases Preparation Progression-Free Survivals Proliferating Proteins Randomized Recurrence Recurrent disease Refractory Regulation Route SHetA2 Schedule Serous Specimen Stress Systems Biology TP53 gene Testing The Cancer Genome Atlas Therapeutic Toxic effect Treatment Efficacy Tumor Burden Uterus Woman Xenograft procedure advanced disease biomarker identification cancer cell cancer survival cancer therapy carcinogenesis drug testing endoplasmic reticulum stress first-in-human improved in vivo inhibitor mortalin mortality novel therapeutics overexpression patient prognosis phase III trial preclinical study predictive marker prevent protein complex response side effect standard of care synergism tumor tumor growth

项目摘要

PROJECT SUMMARY The incidence and mortality of endometrial cancer has increased over the past few decades, and is predicted to continue rising. There is significant need for improved therapies with reduced toxicity for women with endometrial cancers that are advanced, recurrent or refractory to standard of care. Endometrial cancer is a heterogeneous disease that has been classified into molecular profile categories with different degrees of patient prognosis. Across these categories, endometrial cancer has the highest rates of mutations in heat shock protein A(HSPA) 5, 8 and 9 genes compared to other The Cancer Genome Atlas-studied cancers. The HSPA5, HSPA8 and HSPA9 genes encode chaperone proteins, Grp78, hsc70 and mortalin, respectively, which become elevated during carcinogenesis to bind and modulate oncoproteins in a way that assures cancer cell survival. Thus, these chaperone/oncoprotein complexes represent differential targets present at higher levels in cancer cells compared to healthy cells. We developed a drug, SHetA2 (NSC 726189), which disrupts these complexes. SHetA2 induces growth arrest, altered metabolism, mitophagy and cell death in endometrial cancer cells, while the effects on healthy cells is limited to G1 cell cycle arrest. Preclinical studies found lack of SHetA2 toxicity, and this drug is now in a Phase 1 clinical trial in advanced, recurrent or persistent gynecologic cancers (NCT04928508). In vivo studies revealed that SHetA2 has complementary activities and efficacies with paclitaxel and cyclin dependent kinase (CDK4/6) inhibitors. In this project, we hypothesize that SHetA2 will safely reduce endometrial cancer tumor burden and complement the efficacies of paclitaxel and CDK4/6 inhibitors without increasing toxicity; the mechanism will be mediated through SHetA2 disruption of HSPA/client protein complexes; and the treatment efficacies will be modulated by mutations in PTEN and TP53 genes. To test this, and optimize SHetA2-based therapies, we propose to study the mechanism of SHetA2 in healthy endometrial cells, endometrial cancer cell lines, and patient derived organoids and xenografts with a range of natural or induced genetic mutations in PTEN and TP53 genes. We will conduct a Phase 1 clinical trial of SHetA2 in combination with paclitaxel in advanced, recurrent or persistent endometrial cancer patients; a Phase 2 expansion will evaluate response. Using specimens from this and other trials, we will test the hypothesis that mortalin co-localization with the Mps1 kinase or p53 at the centrosome correlates with poor or improved response, respectively, of paclitaxel-treated endometrial cancer patients. In preparation for a future clinical trial, we will use a quantitative systems biology approach that integrates pharmacokinetic, pharmacodynamic and toxicity data to optimize dose and schedule for testing SHetA2 in combination with CDK4/6 inhibitors. The outcome is anticipated to identify biomarkers predictive of which patients will most likely benefit from SHetA2- based therapies, and provide justification and data for development of a randomized Phase 3 trial of a SHetA2 combination anticipated to have an improved therapeutic window over current therapy.

项目总结子宫内膜癌的发病率和死亡率在过去几十年中有所增加，预计继续上升。对于患有子宫内膜症的妇女来说，有必要改进治疗，减少毒性。晚期、复发或难治性癌症。子宫内膜癌是一种异质性肿瘤。已被分类为分子图谱类别的疾病，具有不同程度的患者预后。在这些类别中，子宫内膜癌的热休克蛋白A(HSPA)突变率最高 5、8和9个基因与癌症基因组图谱研究的其他癌症进行比较。HSPA5、HSPA8和 HSPA9基因分别编码伴侣蛋白GRP78、hsc70和mortalin，它们都会升高在癌变过程中以确保癌细胞存活的方式结合和调节癌蛋白。因此，这些伴侣/癌蛋白复合体代表癌细胞中高水平存在的不同靶点与健康细胞相比。我们开发了一种药物SHetA2(NSC 726189)，它可以破坏这些复合体。 SHetA2诱导子宫内膜癌细胞生长停滞、代谢改变、有丝分裂和细胞死亡，而对健康细胞的影响仅限于G1期细胞周期停滞。临床前研究发现SHetA2缺乏毒性，并且该药目前正处于治疗晚期、复发或持续性妇科癌症的第一阶段临床试验。 (NCT04928508)。体内研究表明SHetA2与紫杉醇具有互补的活性和疗效和细胞周期蛋白依赖性激酶(CDK4/6)抑制剂。在本项目中，我们假设SHetA2将安全地减少紫杉醇和CDK4/6抑制剂对子宫内膜癌肿瘤的负担和补充作用增加毒性；其机制将通过SHetA2破坏HSPA/客户蛋白来介导治疗效果将受到PTEN和TP53基因突变的影响。为了测试这一点，并优化基于SHetA2的治疗，我们建议研究SHetA2在健康子宫内膜中的作用机制细胞、子宫内膜癌细胞系、患者来源的器官和异种移植诱发PTEN和TP53基因的遗传突变。我们将在中国进行SHetA2的一期临床试验紫杉醇联合治疗晚期、复发或持续性子宫内膜癌患者：A期 Expansion将评估回应情况。使用这次试验和其他试验的样本，我们将检验这一假设 Mortalin与中心体上的Mps1激酶或P53共定位与较差或改善相关紫杉醇治疗子宫内膜癌患者的疗效。在为未来的临床试验做准备时，我们将使用一种定量系统生物学方法，将药代动力学、药效学和毒性数据，以优化SHetA2与CDK4/6抑制剂联合测试的剂量和时间表。这个预计结果将确定预测哪些患者最有可能受益于SHetA2的生物标志物。基于治疗，并为SHetA2的随机3期试验的开发提供理由和数据联合治疗预计会比目前的治疗方法有更好的治疗窗口。