Leveraging the methionine salvage pathway as a novel therapy for prostate cancer.

 描述(申请人提供)：最近的研究结果表明，在前列腺细胞中发现的多胺生物合成的异常水平，并在前列腺癌(CAP)中加剧，使一碳代谢和蛋氨酸循环紧张，使前列腺上皮细胞对这些代谢途径的扰动高度敏感。多胺的高水平生物合成是由亚精胺/精胺N1-乙酰基转移酶(SSAT)的活性驱动的，它使多胺乙酰化，导致多胺分泌到管腔内，并需要多胺的从头合成来维持细胞内的水平。蛋氨酸挽救途径通过将多胺生物合成过程中丢失的一碳单位重新循环到蛋氨酸循环中，从而补充S-腺苷甲硫氨酸库并保护核苷酸库，从而提供了一种缓解这种代谢性菌株的方法。虽然在许多类型的癌症中，这一途径会因甲硫腺苷磷酸酶(MTAP)基因(位于p16基因座100kb内)的缺失而受到影响，但在CAP中，MTAP的缺失非常罕见。我们的中心想法是通过上调SSAT活性来增加多胺生物合成通量和相关的压力，同时干扰细胞的 通过抑制MSP来缓解压力。本提案的目的是确定单独或联合应用多胺分解代谢上调MSP抑制的治疗潜力，以提高雄激素剥夺疗法(ADT)的临床益处的程度和/或持续时间。中心假说是，由于多胺生物合成的高代谢通量，MSP对CAP至关重要，这种依赖性可以通过增加SSAT的活性来增强。靶向这些通路将为预防或延缓ADT期间的复发提供新的治疗策略。因此，我们建议使用一种联合药理学方法来增加CAP细胞的代谢应激，方法是用多胺类似物处理，通过增加SSAT活性来上调多胺分解代谢，同时通过抑制MTAP来降低细胞缓解这种应激的能力。这一假说将通过追求三个具体目标来检验：在目标1中，我们试图确定MSP抑制和多胺分解代谢增强之间存在协同或相加关系的可能性，以造成代谢危机，并了解药物效应的机制基础。在目标2中，我们将评估在人类细胞系异种移植中产生代谢危机来治疗已建立的雄激素非依赖性CAP的有效性。在目标3中，我们将确定产生代谢危机以防止去势复发进展到ADT复发上限的模型的有效性。这一新方法利用了前列腺上皮细胞中一种固有的代谢菌株，以开发新的治疗策略。这些临床前研究将确定是否可以通过利用现有的代谢菌株(增加多胺分解代谢)来获得治疗效果，同时阻止有助于缓解该菌株的关键挽救途径。

 DESCRIPTION (provided by applicant): Recent findings have shown that the extraordinary level of polyamine biosynthesis found in prostate cells, and accentuated in prostate cancer (CaP), places strain on one-carbon metabolism and the methionine cycle making prostatic epithelial cells highly sensitive to perturbation of these metabolic pathways. The high level of polyamine biosynthesis is driven by the activity of spermidine/spermine N1-acetyltransferase (SSAT), which acetylates the polyamines leading to their secretion into the lumen, and necessitates de novo synthesis of polyamines to maintain intracellular levels. The methionine salvage pathway (MSP) provides a means of mitigating this metabolic strain by recycling the one-carbon unit lost to polyamine biosynthesis back into the methionine cycle, thereby replenishing s-adenosylmethionine (SAM) pools and protecting nucleotide pools. While this pathway is compromised in many types of cancer by deletion of the methylthioadenosine phosphor- ylase (MTAP) gene (located within 100kb of the p16 locus), deletion of MTAP is very rare in CaP. Our central idea is to increase polyamine biosynthetic flux and the associated stress by upregulating SSAT activity, while at the same time interfering with the cells' ability to mitigate the stress by inhibiting the MSP. The objective of the current proposal is to determine the therapeutic potential of polyamine catabolism upregulation MSP inhibition, either alone or in combination, to enhance the extent and/or duration of clinical benefit of androgen deprivation therapy (ADT). The central hypothesis is that the MSP is critical to CaP due to high metabolic flux through polyamine biosynthesis, and that this dependence can be enhanced by increasing the activity of SSAT. Targeting these pathways will provide novel therapeutic strategies to prevent or delay recurrence during ADT. Therefore, we propose to use a combination pharmacological approach to increase metabolic stress of CaP cells by treating with a polyamine analogue to upregulate polyamine catabolism by increasing SSAT activity, while at the same time reducing the cells' ability to mitigate that stress by inhibiting MTAP. The hypothesis will be tested by pursuing three specific aims: In Aim 1 we seek to determine the potential for synergistic or additive relationships between MSP inhibition and enhancement of polyamine catabolism to create a metabolic crisis and to understand the mechanistic basis of drug effects. In Aim 2 we will evaluate the efficacy of generating a metabolic crisis to treat established androgen independent CaP in human cell line xenografts. In Aim 3 we will determine the effectiveness of generating a metabolic crisis to prevent castration recurrence models of progression to ADT-recurrent CaP. This novel approach takes advantage of an inherent metabolic strain accentuated in prostatic epithelial cells in order to develop novel therapeutic strategies. These pre-clinical studies will determine if therapeutic efficacy can be obtained through leveraging of already existing metabolic strain by adding to it (increasing polyamine catabolism) while simultaneously blocking a critical salvage pathway that helps to mitigate that strain.