HMGA2 mediates resistance to therapy in prostate cancer

HMGA2 介导前列腺癌治疗耐药

• 批准号: 10622747
• 负责人: Valerie Odero-Marah
• 金额: $ 15.1万
• 依托单位: MORGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622747
• 关键词: 3' Untranslated Regions; Address; Androgen Receptor; Binding; Biological Markers; Cancer Etiology; Cancer Patient; Carcinoma; Castration; Cell Line; Cell Nucleus; Cells; Cessation of life; Clinical; Clinical Trials; Combined Modality Therapy; Data; Developing Countries; Diagnosis; Drug Combinations; Drug resistance; E-Cadherin; Epithelium; Human; Invaded; LNCaP; Length; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mediating; Mesenchymal; Metastatic Prostate Cancer; Mouth Carcinoma; Mus; Neoplasm Metastasis; Neuroendocrine Prostate Cancer; Neurosecretory Systems; Organoids; Paclitaxel; Pancreas; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Prostate; Publishing; Receptor Activation; Regimen; Reporting; Resistance; Sequential Treatment; Small Interfering RNA; Stomach; Testing; Tissue Sample; Toxic effect; United States; Vimentin; abiraterone; advanced prostate cancer; androgen biosynthesis; aurora kinase A; cBioPortal; cancer cell; castration resistant prostate cancer; cell growth; chemotherapy; cohort; docetaxel; enzalutamide; hormone therapy; in vivo; kinase inhibitor; lung Carcinoma; malignant breast neoplasm; men; migration; neoplastic cell; novel; overexpression; prevent; receptor expression; therapy resistant; transcription factor

PROJECT SUMMARY Epithelial-mesenchymal transition (EMT) is well characterized in epithelial cancers where tumor cells at the invasive front lose epithelial markers such as E-cadherin, gain mesenchymal markers such as vimentin, to promote invasion, migration and subsequent metastasis; it can be promoted by transcription factors such as High Mobility Group A2 (HMGA2). Treatment for metastatic PCa is problematic, especially if it becomes metastatic and castration-resistant (mCRPC). Current first-line hormone therapy for metastatic PCa includes abiraterone that inhibits androgen biosynthesis, and enzalutamide that binds to androgen receptor (AR) and prevents its translocation to the nucleus, while in less developed nations where these novel hormonal therapies are not available, docetaxel is the main therapy. However, resistance to these drugs usually develops and EMT has been shown to contribute to this resistance. Neuroendocrine advanced PCa has been treated with Aurora A kinase inhibitor, alisertib/MLN8237, while combination treatment of MLN8237 with abiraterone in mCRPC in 9 patients was terminated due to toxicity and lack of clinical benefit. Interestingly, MLN8237 inhibits EMT in pancreatic and ovarian cancer cells. Overexpression of HMGA2 in pancreatic, lung carcinomas and carcinoma of oral cavity, and prostate cancer is published where it promotes EMT, while we reported that full-length but not truncated (missing 3’UTR) HMGA2 promotes EMT. Our preliminary data from cBioportal in 444 metastatic PCa patients shows that 3% of the patients show HMGA2 amplification. 43% of these metastasis patients with HMGA2 amplification received abiraterone treatment, while 21% received enzalutamide and 36% received MLN8237. Interestingly, we further show that MLN8237 is able to inhibit cell growth in LNCaP cells overexpressing both full-length/wild-type and truncated HMGA2 as well as LNCaP Neo control cells. However, only wild-type HMGA2 confers resistance to docetaxel and enzalutamide concomitant with increased AR expression and localization within the nucleus, compared to cells expressing truncated HMGA2. The hypothesis is that wild-type HMGA2 confers resistance to docetaxel and hormone therapy in metastatic PCa via AR-dependent and -independent mechanisms that may be overcome by treatment with MLN8237, or pre-treatment with MLN8237 to first inhibit EMT followed by treatment with hormone therapy. We will confirm resistance to docetaxel, enzalutamide and abiraterone in several AR- dependent and AR-independent cell lines expressing HMGA2 by manipulating HMGA2 expression and analyzing HMGA2 expression and localization in cells resistant to these drugs and elucidate the mechanisms. We will also examine whether MLN8237 inhibits EMT in PCa and the effect of single and combination treatments in vivo. Our studies will be impactful in showing that wild-type HMGA2 can be used as a biomarker to avoid treatment with hormonal therapy and instead utilize MLN8237 or pre-treat with MLN8237 to inhibit EMT followed by treatment with docetaxel or enzalutamide.

项目摘要 上皮-间充质转化（EMT）在上皮癌中得到了很好的表征，其中肿瘤细胞在上皮细胞中， 侵袭性前部丢失上皮标记物如E-钙粘蛋白，获得间充质标记物如波形蛋白， 促进侵袭、迁移和随后的转移;它可以由转录因子如 高迁移率族A2（HMGA 2）。转移性PCa的治疗是有问题的，特别是如果它成为 转移性和去势抵抗性（mCRPC）。目前转移性PCa的一线激素治疗包括 抑制雄激素生物合成的阿比特龙和结合雄激素受体（AR）的恩杂鲁胺， 阻止其易位到细胞核，而在欠发达国家，这些新的激素 治疗方法不可用，多西他赛是主要治疗方法。然而，对这些药物的耐药性通常 发展和EMT已被证明有助于这种阻力。神经内分泌晚期前列腺癌 用Aurora A激酶抑制剂alisertib/MLN 8237治疗，而MLN 8237与 9例mCRPC患者的阿比特龙治疗因毒性和缺乏临床获益而终止。有趣的是， MLN 8237抑制胰腺癌和卵巢癌细胞中的EMT。胰腺、肺中HMGA 2的过度表达 癌和口腔癌，前列腺癌是出版的，其中它促进EMT，而我们 报道全长但未截短（缺失3 'UTR）的HMGA 2促进EMT。我们的初步数据来自 cBioportal在444例转移性PCa患者中显示，3%的患者显示HMGA 2扩增。43%的 这些具有HMGA 2扩增的转移患者接受阿比特龙治疗，而21%的患者接受阿比特龙治疗。 Enzalutamide和36%接受MLN 8237。有趣的是，我们进一步表明MLN 8237能够抑制细胞增殖， 在过表达全长/野生型和截短型HMGA 2以及LNCaP Neo的LNCaP细胞中生长 对照细胞。然而，只有野生型HMGA 2对多西他赛和伴随的Enzalutamide产生耐药性， 与表达截短型RNA的细胞相比， HMGA2.假设野生型HMGA 2赋予对多西他赛和激素治疗的抗性 在转移性PCa中通过AR依赖性和非依赖性机制， 用MLN 8237处理，或先用MLN 8237预处理以抑制EMT，然后用 激素疗法我们将在几例AR患者中证实对多西他赛、Enzalutamide和阿比特龙的耐药性， 通过操纵HMGA 2表达表达的AR依赖性和AR非依赖性细胞系， 分析HMGA 2在对这些药物耐药的细胞中的表达和定位，并阐明其机制。 我们还将检查MLN 8237是否抑制PCa中的EMT以及单药和联合用药的作用。 体内治疗。我们的研究将有力地表明野生型HMGA 2可用作生物标志物。 避免使用激素治疗，而是使用MLN 8237或用MLN 8237预处理以抑制 EMT后接受多西他赛或Enzalutamide治疗。