Effects of Arginine Depletion Combined with Platinum-Taxane Chemotherapy in Aggressive Variant Prostate Cancers (AVPC)

项目摘要/摘要 不同前列腺癌中的雄激素占疾病致死率的很大比例，并具有 治疗选择有限，部分原因是缺乏识别的生物标记物。解决未得到满足的需求 为这一亚群开发有效的治疗方法，我们定义了侵袭性变异型前列腺癌(Avpc)。 标准。通过在小鼠身上进行的一系列前瞻性试验和研究，我们表明AVPC标准可以丰富 对于对雄激素抑制反应不佳并从添加卡铂中获益的前列腺癌 卡巴紫杉醇。在最近的试验中，我们检查了PARP抑制剂的维持和抗PD1的作用 对男性动静脉癌患者化疗主干的抑制作用。早期数据显示，在 这些增加的结果，但许多患有AVPC的男性仍在快速进步。我们的总体目标是 得出合理的、基于生物的联合疗法，有效地治疗AVPC。 我们试验参与者的样本分析和临床前研究都集中在改变的精氨酸上。 代谢是雄激素非依赖性前列腺癌生物学中的关键代谢途径。我们还发现 铂类药物诱导AVPC细胞株精氨酸琥珀酸合成酶1(ASS1)沉默的证据 和病人样本。ASS1缺乏症使细胞依赖细胞外精氨酸，因此对 使用聚乙二醇化精氨酸脱亚胺酶(ADI-PEG20)等药物来消耗精氨酸。ADI-PEG20耗尽 血清精氨酸水平，在几种恶性肿瘤中具有活性(单独和联合化疗)，以及 具有免疫调节作用。然而，血清精氨酸耗竭对肿瘤内代谢产物的影响 患者体内的水平尚不清楚，其对人类免疫肿瘤微环境(TME)的影响仍然存在 人们对此知之甚少。我们假设ADI-PEG20的加入将提高 卡铂+卡氮紫杉醇通过改变小鼠肿瘤内精氨酸代谢和免疫功能 AVPC TME。 在目标1中，我们将进行I/II阶段剂量递增试验，以确定最佳剂量(就安全性和 ADI-PEG20联合卡铂+卡氮紫杉醇治疗男性AVPC的疗效)。在AIM 2中，外周血 以及从试验参与者在基线、治疗1个周期和6个周期后获得的转移肿瘤活检， 在PDX和同基因小鼠模型中的平行时间点，将用于测量以下各项之间的关联： (A)血清精氨酸和瓜氨酸水平，(B)瘤内精氨酸水平，(C)ASS1表达，以及(D) 其他精氨酸代谢酶的表达，以及(E)结果。在目标3中，我们将研究 治疗对TME内免疫特性和免疫细胞分布的影响。 我们的研究将全面评估血清精氨酸耗竭对免疫系统的影响。 和非免疫性AVPC TME，阐明了ADI-PEG20和细胞毒之间的协同机制 化疗，并最终为动静脉癌的治疗确定合理组合的优先顺序。

PROJECT SUMMARY/ABSTRACT Androgen indifferent prostate cancers account for a large proportion of the disease lethality and have limited therapy options, partly due to the lack of identifying biomarkers. To address the unmet need of developing effective therapies for this subset, we defined the aggressive variant prostate cancers (AVPC) criteria. Through a series of prospective trials and studies in mice, we showed that the AVPC criteria can enrich for prostate cancers that respond poorly to androgen inhibition and benefit from adding carboplatin to cabazitaxel. In recent trials we examined the contribution of PARP inhibitor maintenance, and of anti-PD1 inhibition to the chemotherapy backbone in men with AVPC. Early data show meaningful improvements in outcomes with these additions, but many men with AVPC are still progressing rapidly. Our overall goal is to arrive at rational, biologically-based combination therapies that effectively treat the AVPC. The analysis of samples from our trial participants, and preclinical studies, converge on altered arginine metabolism as a key metabolic pathway in androgen-indifferent prostate cancer biology. We also found evidence of argininosuccinate synthase 1 (ASS1) silencing with platinum chemotherapy in AVPC cell lines and patient samples. ASS1 deficiency renders cells dependent on extracellular arginine, and thus sensitive to arginine depletion with agents such as PEGylated arginine deiminase (ADI-PEG20). ADI-PEG20 depletes serum arginine levels, has activity in several malignancies (alone and in combination with chemotherapy), and has immunomodulatory effects. However, the effects of serum arginine depletion on intratumoral metabolite levels in patients are unknown, and its effects on the human immune tumor microenvironment (TME) remain poorly understood. We hypothesize that the addition of ADI-PEG20 will improve the efficacy of carboplatin+cabazitaxel by modifying intratumoral arginine metabolism and immune profiles in the AVPC TME. In AIM 1, we will conduct a phase I/II dose escalation trial to identify the optimal dose (in terms of safety and efficacy) of ADI-PEG20 to combine with carboplatin+cabazitaxel in men with AVPC. In AIM 2, peripheral blood and metastatic tumor biopsies obtained from trial participants at baseline, after 1 and after 6 cycles of treatment, and at parallel time-points in PDX and syngeneic mouse models, will be used to measure associations between: (a) serum levels of arginine and citrulline, (b) intratumoral levels of arginine, (c) ASS1 expression, and (d) the expression of other arginine metabolism enzymes, and (e) outcomes. In AIM 3 we will examine the effects of treatment on immune profiles and immune cell distribution within the TME. Our studies will provide a comprehensive evaluation of the effects of serum arginine depletion on the immune and non-immune AVPC TME, shed light on the mechanisms of synergy between ADI-PEG20 and cytotoxic chemotherapy, and ultimately, serve to prioritize rational combinations for the treatment of the AVPC.