Novel Prostate cancer therapy based on m-aconitase inhibition

基于 m-乌头酸酶抑制的新型前列腺癌疗法

• 批准号: 10580844
• 负责人: ANNA MOORE
• 金额: $ 18.11万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580844
• 关键词: Aconitate Hydratase; Address; Advanced Malignant Neoplasm; Aerobic; Animal Model; Cancer Patient; Cell Death; Cells; Cessation of life; Citrates; Citric Acid Cycle; Development; Down-Regulation; Effectiveness; Enzymes; Epithelial Cells; FOLH1 gene; Formulation; Glucose; Goals; Hormones; Human; Image; In Vitro; Investigation; Lip structure; Liposomes; Liquid substance; Magnetic Resonance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Monitor; Neoplasm Metastasis; Nonmetastatic; Patient observation; Patients; Phenotype; Pilot Projects; Production; Property; Prostate; Prostate Cancer therapy; Prostatic; Radiation therapy; Radical Prostatectomy; Reaction; Refractory; Reporter; Testing; Treatment Efficacy; Treatment Protocols; Zinc; advanced disease; cancer cell; chemoradiation; deprivation; design; energy efficiency; hormone therapy; image guided; in vivo; inhibitor; men; mortality; mouse model; novel; novel therapeutic intervention; optical imaging; oxidation; prostate cancer cell; prostate cancer cell line; prostate cancer model; side effect; targeted imaging; tumor; zinc-binding protein

ABSTRACT Treatment options for patients with early-stage prostate cancer include mostly watchful waiting, radical prostatectomy or radiation therapy, whereas for patients with advanced disease hormone therapy followed by chemotherapy/radiotherapy are the preferred options. However, all of these options suffer from very serious side effects. While early-stage cancers can be addressed with radical prostatectomy, this is not the case for advanced cancers at hormone refractory and/or metastatic stages. Approaches with lesser side effects and more effectiveness are needed, especially for the latter scenarios. Our proposed approach takes advantage of the innate property of the prostate gland, which is accumulation of enormously high levels of citrate and zinc by the prostate glandular epithelial cells. Zinc serves as an inhibitor of m-aconitase, the enzyme, which controls the first reaction for the entry of citrate into the Krebs cycle. The Krebs cycle in these cells is truncated, and synthesized citrate accumulates for secretion into prostatic fluid. However, in prostate cancer cells the ability to accumulate zinc is lost due to downregulation of zinc transporter. This deficiency leads to normalization of m-aconitase activity and oxidation of citrate via a functional Krebs cycle resulting in 38 ATP/glucose compared to 14 ATP/glucose produced from the aerobic oxidation of glucose in normal prostate cells. Thus, the malignant cells become energy-efficient in contrast to the energy-inefficient, specialized citrate-producing prostate epithelial cell and change their phenotype to a “citrate-oxidizing”. In this study we propose to inhibit m-aconitase with the goal to reverse the “citrate-oxidizing” phenotype in prostate cancer. This will be done by delivering zinc to tumors in vivo using prostate specific membrane antigen (PSMA)-targeted image-guided liposomes loaded with zinc. We expect that inhibition of m-aconitase by zinc will cause a dramatic decrease in energy production by cancer cells, which will ultimately lead to energy deprivation and cell death. Since monitoring the delivery of Zn-containing liposomes will provide us with opportunity to alter formulation in the course of investigation and adjust treatment regimen, the proposed liposomes will contain imaging reporters for magnetic resonance and optical imaging. We propose to synthesize and test Zn-containing PSMA-specific image-guided liposomes first in vitro and then in pilot studies in vivo in non-metastatic and metastatic mouse models of prostate cancer. The latter is of high significance since it is the advanced stage that causes high mortality in prostate cancer patients.

抽象的 早期前列腺癌患者的治疗选择主要包括观察等待、根治性治疗 前列腺切除术或放射治疗，而对于晚期疾病患者，激素治疗随后进行 化疗/放疗是首选选择，但是所有这些选择都有非常严重的副作用。 虽然早期癌症可以通过根治性前列腺切除术来治疗，但晚期癌症却并非如此。 副作用较少且较多的癌症治疗方法。 需要有效性，特别是对于后一种情况。 我们提出的方法利用了前列腺的固有特性，即积累 前列腺上皮细胞产生极高水平的柠檬酸盐和锌，锌起到抑制剂的作用。 间乌头酸酶，控制柠檬酸进入克雷布斯循环的第一个反应。 这些细胞中的循环被截断，合成的柠檬酸盐积累并分泌到前列腺液中。 在癌细胞中，由于锌转运蛋白的下调，积累锌的能力丧失。 缺乏导致间乌头酸酶活性正常化和通过功能性克雷布斯循环柠檬酸氧化 与葡萄糖有氧氧化产生的 14 ATP/葡萄糖相比，产生 38 ATP/葡萄糖 因此，与能量低效的细胞相比，恶性细胞变得能量高效。 专门产生柠檬酸盐的前列腺上皮细胞，并将其表型改变为“柠檬酸盐氧化”。 在这项研究中，我们建议抑制 m-乌头酸酶，目的是逆转“柠檬酸氧化”表型 这将通过使用前列腺特异性膜抗原将锌递送至体内肿瘤来完成。 (PSMA) 靶向图像引导脂质体负载锌，我们预计锌会抑制 m-乌头酸酶。 导致癌细胞产生的能量急剧减少，最终导致能量匮乏 因为监测含锌脂质体的递送将为我们提供改变的机会。 在研究和调整治疗方案的过程中制定制剂，建议的脂质体将包含 我们建议合成和测试含锌成像。 PSMA 特异性图像引导脂质体首先在体外进行，然后在非转移性和非转移性体内进行试点研究 前列腺癌的转移性小鼠模型具有重要意义，因为它是晚期。 导致前列腺癌患者的高死亡率。