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.

项目总结/文摘