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

 描述（由申请人提供）：最近的发现表明，在前列腺细胞中发现的并且在前列腺癌（CaP）中加重的多胺生物合成的异常水平对一碳代谢和甲硫氨酸循环施加压力，使得前列腺上皮细胞对这些代谢途径的扰动高度敏感。高水平的多胺生物合成是由亚精胺/精胺N1-乙酰转移酶（SSAT）的活性驱动的，其使多胺乙酰化，导致其分泌到管腔中，并且需要多胺的从头合成以维持细胞内水平。甲硫氨酸补救途径（MSP）通过将多胺生物合成损失的一碳单元再循环回到甲硫氨酸循环中，从而补充s-腺苷甲硫氨酸（SAM）库并保护核苷酸库，提供了减轻这种代谢菌株的手段。虽然在许多类型的癌症中，该途径由于甲基硫代腺苷磷酸化酶（MTAP）基因（位于p16基因座的100 kb内）的缺失而受到损害，但MTAP的缺失在CaP中非常罕见。我们的中心思想是通过上调SSAT活性来增加多胺生物合成通量和相关的压力，同时干扰细胞的能力， 通过抑制MSP来减轻压力。本提案的目的是确定单独或组合的多胺激动剂上调MSP抑制的治疗潜力，以增强雄激素剥夺疗法（ADT）的临床益处的程度和/或持续时间。中心假设是，MSP是至关重要的钙磷由于高代谢通量通过多胺生物合成，这种依赖性可以通过增加SSAT的活性增强。靶向这些通路将提供新的治疗策略，以预防或延迟ADT期间的复发。因此，我们提出使用组合药理学方法来增加CaP细胞的代谢应激，通过用多胺类似物处理以通过增加SSAT活性上调多胺催化剂，同时通过抑制MTAP降低细胞减轻该应激的能力。该假设将通过追求三个具体目标进行测试：在目标1中，我们试图确定MSP抑制和多胺催化剂增强之间的协同或相加关系的潜力，以产生代谢危机，并了解药物作用的机制基础。在目标2中，我们将评估产生代谢危机以治疗人细胞系异种移植物中已建立的雄激素非依赖性CaP的功效。在目标3中，我们将确定产生代谢危机以防止进展为ADT复发性CaP的去势复发模型的有效性。这种新方法利用了前列腺上皮细胞中固有的代谢应变，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添加（增加多胺催化剂）来利用已经存在的代谢菌株，同时阻断有助于减轻该菌株的关键补救途径来获得治疗效果。

 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.