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

精氨酸消耗联合铂类紫杉烷化疗对侵袭性变异前列腺癌 (AVPC) 的影响

• 批准号: 10715329
• 负责人: Ana Aparicio
• 金额: $ 63.66万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10715329
• 关键词: Address; Androgens; Antibodies; Antitumor Response; Arginine; Arginine deiminase; Biological Markers; Biopsy; CD8-Positive T-Lymphocytes; Cancer Biology; Carboplatin; Cell model; Cell physiology; Cells; Citrulline; Clinical Data; Clinical Research; Clinical Trials; Combination Drug Therapy; Combined Modality Therapy; Cytotoxic Chemotherapy; Data; Development; Disease; Dose; Elements; Enzymes; Epithelium; Evaluation; Goals; Human; Immune; Immune system; Immunohistochemistry; Immunology; Ions; Maintenance; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Chromatography; Mass Spectrum Analysis; Measures; Mediating; Metabolic Pathway; Metabolism; Mus; Neoplasm Metastasis; Nitric Oxide; Outcome; Participant; Pathway interactions; Patients; Phagocytosis; Phase; Phase I/II Trial; Phenotype; Platinum; Poly(ADP-ribose) Polymerase Inhibitor; Polyamines; Population; Positioning Attribute; Pre-Clinical Model; Prognosis; Proteins; Reporting; Role; Safety; Sampling; Series; Serum; Signal Pathway; Signal Transduction; Signaling Molecule; Subjects Selections; T cell infiltration; Technology; Time; Tissues; Tumor-associated macrophages; Variant; Vertebral column; Virulence; advanced prostate cancer; anti-PD-1; argininosuccinate synthase; biomarker identification; chemotherapy; digital; effective therapy; effector T cell; experimental study; extracellular; immunoregulation; improved; inhibitor; men; mouse model; peripheral blood; pre-clinical; preclinical study; prospective; prostate cancer cell; prostate cancer cell line; response; single-cell RNA sequencing; synergism; targeted treatment; taxane; treatment effect; trial design; tumor; tumor metabolism; tumor microenvironment; tumor-immune system interactions

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.

项目摘要/摘要 雄激素冷漠的前列腺癌占疾病杀伤力的很大比例，并且具有 有限的治疗选择，部分是由于缺乏识别生物标志物。解决未满足的需求 为此子集开发有效的疗法，我们定义了侵略性变体前列腺癌（AVPC） 标准。通过一系列的前瞻性试验和研究，我们表明AVPC标准可以丰富 对于前列腺癌，对雄激素抑制作用反应不佳，并从将卡铂添加到 Cabazitaxel。在最近的试验中，我们检查了PARP抑制剂维持和抗PD1的贡献 抑制AVPC男性的化学疗法主链。早期数据显示有意义的改进 这些增加的结果，但是许多患有AVPC的男性仍在迅速发展。我们的总体目标是 到达有效治疗AVPC的理性，基于生物学的组合疗法。 对我们试验参与者的样品和临床前研究的分析，会收敛于改变的精氨酸 代谢作为雄激素诱导前列腺癌生物学的主要代谢途径。我们还发现 用AVPC细胞系中铂化学疗法的精氨酸合酶1（ASS1）沉默的证据 和患者样品。 ASS1缺乏使细胞依赖细胞外精氨酸，因此对 精氨酸的耗竭，如叶酸酯蛋白脱节酶（ADI-PEG20）。 ADI-PEG20耗尽 血清精氨酸水平，在几种恶性肿瘤中具有活性（单独并与化学疗法结合使用），并且 具有免疫调节作用。但是，血清精氨酸耗竭对肿瘤内代谢产物的影响 患者的水平尚不清楚，其对人免疫肿瘤微环境（TME）的影响仍然 理解不佳。我们假设添加ADI-PEG20将提高 通过修改肿瘤内精氨酸代谢和免疫谱，卡铂+cabazitaxel AVPC TME。 在AIM 1中，我们将进行I/II期剂量升级试验以确定最佳剂量（就安全性和 ADI-PEG20的功效与AVPC男性中的卡泊蛋白+cabazitaxel结合使用。在AIM 2中，外围血 以及从基线，1和6个周期后从试验参与者获得的转移性肿瘤活检， 在PDX和Syngeneic小鼠模型中的并行时间点上，将用于测量以下之间的关联： （a）精氨酸和瓜氨酸的血清水平，（b）精氨酸的肿瘤内水平，（c）ASS1表达，（d） 其他精氨酸代谢酶的表达，以及（e）结果。在AIM 3中，我们将研究 TME内的免疫谱和免疫细胞分布进行治疗。 我们的研究将对血清精氨酸耗竭对免疫的影响进行全面评估 和非免疫AVPC TME，阐明了ADI-PEG20和细胞毒性之间的协同作用机理 化学疗法，最终，有助于优先考虑治疗AVPC的理性组合。