Multifunctional Regulation of Prostate Cancer Metabolism by Sigma1 Modulators

摘要：前列腺癌(PCa)是一种高度适应性疾病。前列腺癌的一线治疗是雄激素 剥夺。然而，抵抗力总是会出现，导致称为抗阉割的Pca的致命阶段 (CRPC)。即使当前标准的护理药物阿比特龙和阿比特龙实现了深刻的AR靶向 苯扎鲁胺、CRPC仍无法治愈。CRPC具有多重补偿信号的特点 其机制包括PI3K/Akt/mTOR信号的相互激活和AR-ErbB受体的串扰。 值得注意的是，这些路径汇聚在信令网络、反馈环路和细胞机制上 介导致癌脂质代谢，它现在被认为是CRPC生长和 进步。抗肿瘤疗效的有意义的改善可能需要新的策略， 同时瞄准AR轴和CRPC所依赖的代偿信号通路网络。 我们已经确定Sigma1是一种多功能支架蛋白，在PCa中异常表达，并且 它是前列腺癌细胞生长、增殖所必需的。Sigma1变构调控肿瘤特异性相关 参与驱动致癌脂质代谢的蛋白质，包括AR和ErbB受体。Sigma1还调节 细胞内脂和蛋白质的动态平衡途径，并在支持增加的需求中发挥关键作用 脂肪和蛋白质的合成与肿瘤的生长有关。我们已经开发了一系列新颖的小分子 Sigma1的抑制剂，破坏脂质稳态并诱导AR和ErbB受体的靶向降解 在体外和体内均能抑制PCA的生长，对正常细胞的毒性最小。这个 在这项提案中解决的首要问题是如何针对致命的CRPC 对AR靶向治疗产生抵抗力。我们假设Sigma1作为一个多功能的纽带 Pca中致癌驱动蛋白和脂代谢之间的关系，因此Sigma1抑制不仅扰乱了 肿瘤生长和脂质代谢的关键驱动因素(AR、ErbB)，但也抑制其下游和收敛 小路。在目标1中，我们将定义一个新的Sigma1-AR-ErbB/PI3K/mTOR-脂代谢途径和反馈 在CRPC中使用ErbB/PI3K信令的环路。我们将展示Sigma1抑制剂的抗肿瘤效果 在前列腺癌中是由于抑制了这一途径以及关键的汇聚和互补细胞的破坏 脂肪代谢对前列腺癌生长至关重要的过程。在目标2中，我们将演示Sigma1的有效性 包含基因和表型的患者来源异种移植(PDX)模型队列中的抑制 采用体外有机物和体内肿瘤模型研究CRPC的异质性。在前列腺癌中抑制Sigma1代表 一种新的治疗方法，针对多种相互依赖的机制参与CRPC进展和 阻力的发展，为设计纵横结合提供了合理依据 治疗策略，以阻止增强的脂代谢，燃料致命的，治疗难治的CRPC。

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.