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: 10435673
• 负责人: ANNA MOORE
• 金额: $ 23.5万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10435673
• 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; Lead; Lip structure; Liposomes; Liquid substance; Magnetic Resonance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Monitor; Neoplasm Metastasis; Nonmetastatic; Oxides; 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; base; cancer cell; chemotherapy; deprivation; design; 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 metastasis; 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包括大部分等待，激进 前列腺切除术或放射疗法，而对于患有晚期疾病疗法的患者然后 化学疗法/放疗是首选的选择。但是，所有这些选择都遭受非常严重的一面 效果。虽然早期癌症可以用根治性的前列腺切除术来解决，但事实并非如此 同性恋和/或转移阶段的癌症。副作用较小，更多 需要有效性，尤其是对于后一种情况。 我们提出的方法利用了前列腺的先天财产，这是 前列腺腺上皮细胞的柠檬酸盐和锌非常高。锌作为抑制剂 M- aconitase酶，该酶控制着将柠檬酸盐进入克雷布斯循环的第一反应。 这些细胞中的循环被截断，合成的柠檬酸盐会积聚为前列腺液中的分泌。然而， 在前列腺癌细胞中，由于锌转运蛋白的下调，积累锌的能力丧失。这 缺乏导致通过功能性克雷布斯循环的m- aconitase活性的标准化和柠檬酸盐的氧化 导致38个ATP/葡萄糖，而14个ATP/葡萄糖是由葡萄糖的有氧氧化产生的 正常的前列腺细胞。这，与能量智能相比，恶性细胞变得能有效， 产生柠檬酸盐的专业前列腺上皮细胞，并将其表型更改为“柠檬酸盐氧化”。 在这项研究中，我们建议抑制M- aconitase，以扭转“柠檬酸氧化”表型的目标 前列腺癌。这将通过使用前列腺特异性膜抗原向体内肿瘤传递锌来完成 （PSMA）靶向的图像引导的脂质体装有锌。我们期望锌对M- aconitase抑制会 导致癌细胞的能源产生急剧下降，这最终会导致能量剥夺 和细胞死亡。由于监测含锌的脂质体的交付将为我们提供更改的机会 公式在投资和调整治疗方案中，拟议的脂质体将包含 磁共振和光学成像的成像记者。我们建议合成和测试含锌 PSMA特异性图像引导的脂质体首先在体外，然后在非转移性的体内进行试验研究 前列腺癌的转移小鼠模型。后者具有很高的意义，因为它是高级阶段 在前列腺癌患者中导致高死亡率。