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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要雄激素无关的前列腺癌在疾病致死率中占很大比例，并且治疗选择有限，部分原因是缺乏可识别的生物标志物。为了解决未满足的需求为了针对这一亚型开发有效的疗法，我们定义了侵袭性变异前列腺癌（AVPC）标准。通过一系列小鼠前瞻性试验和研究，我们表明 AVPC 标准可以丰富对于对雄激素抑制反应不佳并通过添加卡铂获益的前列腺癌卡巴他赛。在最近的试验中，我们研究了 PARP 抑制剂维持和抗 PD1 的贡献抑制 AVPC 男性的化疗骨干。早期数据显示显着改善这些补充的结果，但许多患有 AVPC 的男性仍然进展迅速。我们的总体目标是找到有效治疗 AVPC 的合理的、基于生物学的联合疗法。对我们试验参与者的样本分析和临床前研究集中在改变的精氨酸上代谢作为雄激素无关的前列腺癌生物学中的关键代谢途径。我们还发现 AVPC 细胞系中铂类化疗导致精氨基琥珀酸合酶 1 (ASS1) 沉默的证据和患者样本。 ASS1 缺陷使细胞依赖于细胞外精氨酸，从而对使用聚乙二醇化精氨酸脱亚胺酶 (ADI-PEG20) 等试剂消耗精氨酸。 ADI-PEG20 耗尽血清精氨酸水平，对多种恶性肿瘤具有活性（单独使用或与化疗联合使用），并且具有免疫调节作用。然而，血清精氨酸消耗对瘤内代谢物的影响患者体内的水平尚不清楚，其对人体免疫肿瘤微环境（TME）的影响仍然存在不太了解。我们假设添加 ADI-PEG20 将提高功效卡铂+卡巴他赛通过改变瘤内精氨酸代谢和免疫特征 AVPC TME。在AIM 1中，我们将进行I/II期剂量递增试验，以确定最佳剂量（在安全性和 ADI-PEG20 与卡铂+卡巴他赛联合治疗男性 AVPC 的疗效）。在 AIM 2 中，外周血以及在基线、1个和6个治疗周期后从试验参与者获得的转移性肿瘤活检，在 PDX 和同基因小鼠模型的平行时间点，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) 精氨酸的瘤内水平，(c) ASS1 表达，以及 (d) 其他精氨酸代谢酶的表达，以及 (e) 结果。在 AIM 3 中，我们将检查以下效果：对 TME 内免疫特征和免疫细胞分布的治疗。我们的研究将对血清精氨酸消耗对免疫系统的影响进行全面评估和非免疫 AVPC TME，揭示了 ADI-PEG20 和细胞毒性之间的协同机制化疗最终有助于优先考虑合理的组合治疗 AVPC。