Multifunctional Regulation of Prostate Cancer Metabolism by Sigma1 Modulators

Sigma1 调节剂对前列腺癌代谢的多功能调节

基本信息

批准号：
10582517
负责人：
Felix Jinhyun Kim
金额：
$ 61.71万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-13 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10582517
关键词：
Address Androgen Receptor Androgens Automobile Driving Autophagocytosis Bioenergetics Biological Availability Cancer Biology Cancer Cell Growth Cancer Etiology Catabolism Cell Line Cell physiology Cessation of life Cholesterol Clinical Combined Modality Therapy Disease FRAP1 gene Fatty Acids Feedback Genotype Growth Heterogeneity Homeostasis In Vitro Lipids Malignant Neoplasms Malignant neoplasm of prostate Mediating Mediator Metabolic Metabolism Metastatic Prostate Cancer Mitochondria Modeling Nature Normal Cell Oncogenic Oral Organoids PI3K/AKT PIK3CG gene Pathway interactions Phase Phenotype Play Proliferating Prostate Cancer therapy Protein Biosynthesis Proteins Public Health Receptor Cross-Talk Receptor Signaling Refractory Regulation Resistance Resistance development Role Scaffolding Protein Series Signal Pathway Signal Transduction Technology Therapeutic Agents Toxic effect Up-Regulation abiraterone androgen deprivation therapy antitumor effect cancer cell castration resistant prostate cancer cell growth regulation cohort deprivation design enzalutamide fatty acid oxidation improved in vitro Model in vivo inhibitor lipid biosynthesis lipid metabolism lipidomics men novel novel strategies novel therapeutic intervention patient derived xenograft model prostate cancer cell prostate cancer model prostate cancer progression protein metabolism proteostasis receptor resistance mechanism small molecule inhibitor small molecule therapeutics standard of care targeted agent targeted treatment treatment strategy tumor tumor growth tumor metabolism uptake

项目摘要

Abstract: Prostate cancer (PCa) is a remarkably adaptive disease. First line therapy for PCa is androgen deprivation. However, resistance invariably emerges, resulting in a lethal phase termed castration-resistant PCa (CRPC). Even with the profound AR-targeting achieved by current standard of care agents abiraterone and enzalutamide, CRPC remains incurable. CRPC is characterized by multiple compensatory signaling mechanisms including reciprocal activation of PI3K/Akt/mTOR signaling and AR-ErbB receptor cross-talk. Notably, these pathways converge on the signaling networks, feedback loops, and cellular mechanisms that mediate oncogenic lipid metabolism, which is now recognized as a central driver of CRPC growth and progression. Meaningful improvement in anti-tumor efficacy is likely to require novel strategies that simultaneously target the AR axis and the network of compensatory signaling pathways on which CRPC depends. We have identified Sigma1 as a multi-functional scaffolding protein that is aberrantly expressed in PCa and that it is required for PCa cell growth proliferation. Sigma1 allosterically modulates cancer-specific associated proteins involved in driving oncogenic lipid metabolism, including AR and ErbB receptors. Sigma1 also regulates cellular lipid and protein homeostasis pathways, and plays a critical role in supporting the increased demand for lipid and protein synthesis associated with tumor growth. We have developed a series of novel small molecule inhibitors of Sigma1 that disrupt lipid homeostasis and induce targeted degradation of AR and ErbB receptors in PCa cells, resulting in inhibition of PCa growth in vitro and in vivo with minimal toxicity to normal cells. The overarching problem addressed in this proposal is how to target the critical mechanisms by which lethal CRPC becomes resistant to AR-targeted therapy. We hypothesize that Sigma1 serves as a multifunctional nexus between oncogenic driver proteins and lipid metabolism in PCa, such that Sigma1 inhibition disrupts not only key drivers of tumor growth and lipid metabolism (AR, ErbB), but also inhibit their downstream and convergent pathways. In Aim 1 we will define a novel Sigma1-AR-ErbB/PI3K/mTOR-lipid metabolism pathway and feedback loop that engages ErbB/PI3K signaling in CRPC. We will show that the anti-tumor efficacy of Sigma1 inhibitors in PCa is due to suppression of this pathway as well as disruption of key convergent and complementary cellular processes critical for PCa growth fueled by lipid metabolism. In Aim 2 we will demonstrate the efficacy of Sigma1 inhibition in a cohort of patient derived xenograft (PDX) models that encompass the genotypic and phenotypic heterogeneity of CRPC, using in vitro organoid and in vivo tumor models. Inhibition of Sigma1 in PCa represents a novel therapeutic approach that targets multiple, interdependent mechanisms involved in CRPC progression and development of resistance, and it provides a rational basis for designing vertical and horizontal combination treatment strategies to block the enhanced lipid metabolism that fuels lethal, treatment-refractory CRPC.

摘要：前列腺癌（PCA）是一种非常适应性疾病。 PCA的第一线治疗是雄激素剥夺。但是，抗药性总是出现，导致致命的相称为castration耐药性PCA （CRPC）。即使是当前护理人标准的Abiraterone和 enzalutamide，CRPC仍然无法治愈。 CRPC的特征是多重补偿信号传导包括PI3K/AKT/MTOR信号传导和AR-ERBB受体串扰的相互激活的机制。值得注意的是，这些途径在信号网络，反馈回路和细胞机制上收敛介导致癌脂质代谢，现在被认为是CRPC生长和进展。抗肿瘤功效的有意义的改善可能需要新颖的策略同时针对AR轴和CRPC依赖的补偿信号通路网络。我们已经确定Sigma1是一种多功能脚手架蛋白，在PCA中异常表达，并且这是PCA细胞生长增殖所必需的。 Sigma1变构调节癌症特异性相关参与驱动致癌脂质代谢的蛋白质，包括AR和ERBB受体。 Sigma1也会调节细胞脂质和蛋白质稳态途径，并在支持对增加的需求中起着至关重要的作用脂质和蛋白质合成与肿瘤生长有关。我们已经开发了一系列新型的小分子 SIGMA1的抑制剂破坏脂质稳态并诱导AR和ERBB受体的靶向降解 PCA细胞，导致体外和体内PCA生长的抑制作用，对正常细胞的毒性最少。这本提案中解决的总体问题是如何针对致命的CRPC的关键机制对AR靶向疗法具有抵抗力。我们假设Sigma1用作多功能Nexus 在PCA中的致癌驱动蛋白和脂质代谢之间，因此Sigma1抑制不仅会破坏肿瘤生长和脂质代谢的主要驱动因素（AR，ERBB），但也抑制其下游和收敛性途径。在AIM 1中，我们将定义一种新颖的Sigma1-AR-ERBB/PI3K/MTOR-LIPID代谢途径和反馈与CRPC中的ERBB/PI3K信号传递的循环。我们将证明Sigma1抑制剂的抗肿瘤功效在PCA中，是由于抑制此途径以及关键收敛和互补细胞的破坏脂质代谢推动的PCA增长至关重要的过程。在AIM 2中，我们将证明Sigma1的功效包括基因型和表型的患者衍生异种移植（PDX）模型的抑制作用 CRPC的异质性，使用体外器官和体内肿瘤模型。 PCA中SIGMA1的抑制代表一种新型的治疗方法，该方法靶向CRPC进展和阻力的发展，它为设计垂直和水平组合提供了合理的基础治疗策略，以阻止增强的脂质代谢，从而燃烧致命的治疗 - fractractory CRPC。