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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.

项目摘要子宫内膜癌的发病率和死亡率在过去的几十年中有所增加，预计继续上升。对于患有子宫内膜异位症的妇女，晚期、复发性或标准治疗难治性癌症。子宫内膜癌是一种异质性已被分类为具有不同程度的患者预后的分子谱类别的疾病。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个基因与其他癌症基因组研究的癌症相比。HSPA 5、HSPA 8和 HSPA 9基因分别编码伴侣蛋白Grp 78、hsc 70和mortalin，这些蛋白在HSPA 9基因表达水平升高时，在癌发生过程中，以确保癌细胞存活的方式结合和调节癌蛋白。因此这些伴侣蛋白/癌蛋白复合物代表癌细胞中以更高水平存在的差异靶点与健康的细胞相比。我们开发了一种药物SHetA 2（NSC 726189），它可以破坏这些复合物。 SHetA 2诱导子宫内膜癌细胞的生长停滞、代谢改变、线粒体自噬和细胞死亡，而对健康细胞的影响仅限于G1期细胞周期停滞。临床前研究发现缺乏SHetA 2毒性，这种药物目前正处于晚期、复发性或持续性妇科癌症的1期临床试验中（NCT04928508）。体内研究表明，SHetA 2与紫杉醇具有互补的活性和功效和细胞周期蛋白依赖性激酶（CDK 4/6）抑制剂。在这个项目中，我们假设SHetA 2将安全地减少子宫内膜癌肿瘤负荷和补充紫杉醇和CDK 4/6抑制剂的疗效，增加毒性;该机制将通过HSPA/客户蛋白的SHetA 2破坏来介导复合物;并且治疗功效将通过PTEN和TP 53基因中的突变来调节。为了验证这个，并优化基于SHetA 2的治疗方案，我们建议研究SHetA 2在健康子宫内膜中的作用机制细胞、子宫内膜癌细胞系和患者来源的类器官和异种移植物，诱导PTEN和TP 53基因突变。我们将在美国进行SHetA 2的1期临床试验，联合紫杉醇治疗晚期、复发性或持续性子宫内膜癌患者; 2期扩大将评估反应。使用本试验和其他试验的样本，我们将检验以下假设：死亡蛋白与Mps 1激酶或p53在中心体的共定位与不良或改善的反应，分别为紫杉醇治疗的子宫内膜癌患者。为了准备未来的临床试验，我们将使用定量系统生物学方法，整合药代动力学、药效学和毒性数据以优化用于测试SHetA 2与CDK 4/6抑制剂组合的剂量和时间表。的预计结果将确定预测哪些患者最有可能从SHetA 2中获益的生物标志物。的治疗，并提供理由和数据，为开发一个随机的3期试验的SHetA 2 预期该组合相对于当前疗法具有改善的治疗窗。