Unravel a novel metabolic pathway orchestrating prostate cancer progression and therapeutic resistance

揭示协调前列腺癌进展和治疗耐药的新代谢途径

• 批准号: 10374340
• 负责人: Hui-Kuan Lin
• 金额: $ 49.74万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-03 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10374340
• 关键词: AKT Signaling Pathway; Ablation; Androgens; Automobile Driving; Back; Biochemical; Biochemical Genetics; Biological Assay; Cancer Etiology; Cancer Patient; Cell Maintenance; Cell Proliferation; Cell Survival; Cells; Cessation of life; Defect; Development; Drug resistance; Genetic; Goals; Human; Impairment; Inositol; Lead; Light; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolic; Metabolic Pathway; Mitochondria; Neoplasm Metastasis; Oncogenic; Outcome; Pathologic; Patients; Pharmacology; Phosphotransferases; Physiological; Play; Population; Prostate; Prostate Ablation; Prostate Cancer therapy; Proteins; RNA Splicing; Regulation; Reporting; Resistance; Role; Signal Pathway; Signal Transduction; Solid; Specimen; Stem Cell Factor; Testing; Therapeutic; United States; Validation; Variant; Xenograft Model; advanced prostate cancer; aldehyde dehydrogenases; androgen deprivation therapy; assay development; base; cancer drug resistance; cancer stem cell; castration resistant prostate cancer; clinically relevant; clinically significant; druggable target; experimental study; genetic approach; in vivo; innovation; insight; knock-down; men; metabolomics; mouse model; new therapeutic target; novel; overexpression; patient derived xenograft model; prostate cancer cell; prostate cancer progression; resistance mechanism; stem cell biomarkers; stem cell population; stemness; survival outcome; therapeutic target; therapy resistant; transcriptomics; tumor; tumor metabolism

Summary Prostate cancer is the second leading cause of cancer deaths in the United States. While androgen ablation therapy (ABT) is the mainstay of therapy for men with prostate cancer, most patients with prostate cancer will inevitably develop castration-resistant prostate cancer (CRPC), which no longer responds to ABT treatment. Thus, understanding of the mechanisms leading to CRPC and ABT resistance is urgently needed. Several mechanisms account for the occurrence of CRPC, such as activation of 3-kinase/Akt signaling pathway, which plays a critical role in cell proliferation and cell survival, and higher expression of AR and AR splicing variants, which facilitate prostate cancer cell survival under very low androgen concentrations. Of note is that prostate cancer stem cells (PCSCs) also known as cancer initiating cells (CICs), which account for a small cell population prostate cancer cells, are critically involved in the development of CRPC. But how PCSCs are regulated and how they can be pharmacologically targeted are currently not well understood. While several stem cell factors such as SOX2 playing an important role in maintaining PCSC pool and functions are identified, there is no effective strategy to block the action of these proteins in order to eradicate PCSCs within the cancer. Thus, identifying key druggable targets maintaining PCSCs could provide novel paradigms and effective strategies for prostate cancer therapy and overcoming ABT resistance. Our goal in this study is to identify a novel mechanism underlying PCSC maintenance, which could be harnessed to develop an effective strategy for CRPC targeting. Using systematic metabolomics and transcriptomics in conjunction with biochemical validation and in vivo tumor development assays, we unraveled a novel oncogenic and metabolic signaling pathway, which was elevated during ABT treatment and in advanced human prostate cancer, is critical for maintaining the stemness and pool of PCSCs and CRPC development. Of note, we observed aberrant AMPK activation and AMPK-dependent mitochondria fission upon loss of this metabolic signaling, correlated with the defect in stemness and pool of PCSCs and prostate cancer progression. In light of these findings, we hypothesized that this newly discovered metabolic signaling is crucial for restricting aberrant AMPK-dependent mitochondrial fission to maintain the pool and stemness of PCSCs, thereby leading to CRPC and ABT resistance. Our hypothesis has been formulated based on our solid and innovative preliminary results. In this proposal, we proposed three specific aims to test this paradigm-shift hypothesis. Our study has not only revolutionized and significantly advanced our understanding of cancer metabolism in PCSC regulation, but also offered a promising strategy to treat advanced prostate cancer and overcoming ABT resistance.

总结 前列腺癌是美国癌症死亡的第二大原因。当雄激素消融术 前列腺癌的早期症状有哪些？前列腺癌的早期症状有哪些？ 不可避免地发展去势抵抗性前列腺癌（CRPC），其不再对ABT治疗有反应。 因此，迫切需要了解导致CRPC和ABT耐药的机制。几 CRPC的发生机制，例如3-激酶/Akt信号通路的激活， 在细胞增殖和细胞存活中起关键作用，AR和AR剪接变体的更高表达， 其促进前列腺癌细胞在非常低的雄激素浓度下存活。值得注意的是前列腺 癌症干细胞（PCSC）也称为癌症起始细胞（CIC），其占小细胞群 前列腺癌细胞，在CRPC的发展中至关重要。但如何监管PCSC， 目前还不清楚如何将它们作为非目标。虽然一些干细胞因子 例如SOX 2在维护PCSC池和功能方面发挥重要作用， 因此，我们需要一种有效的策略来阻断这些蛋白质的作用，以根除癌症中的PCSC。因此，在本发明中， 确定维持PCSC的关键可药物靶点可以提供新的范例和有效的策略， 前列腺癌治疗和克服ABT耐药。我们在这项研究中的目标是确定一种新的机制， 这可以用来制定针对CRPC的有效战略。 使用系统代谢组学和转录组学结合生物化学验证和体内肿瘤 通过开发试验，我们揭示了一种新的致癌和代谢信号通路， 在ABT治疗期间和晚期人类前列腺癌中， PCSC和CRPC的发展。值得注意的是，我们观察到异常的AMPK激活和AMPK依赖性 线粒体分裂后，这种代谢信号的损失，与缺陷的干和池 PCSC和前列腺癌进展。根据这些发现，我们假设这个新发现的 代谢信号对于限制异常的AMPK依赖性线粒体分裂以维持细胞池至关重要 以及PCSC的干性，从而导致CRPC和ABT抗性。我们的假设是 基于我们扎实创新的初步成果。在这份提案中，我们提出了三个具体目标， 这种范式转换假说。我们的研究不仅彻底改变和显著提高了我们的 了解PCSC调节中的癌症代谢，但也提供了一个有希望的治疗晚期癌症的策略。 前列腺癌和克服ABT耐药性。