Developing therapies to improve enzalutamide in CRPC

开发改善恩杂鲁胺治疗 CRPC 的疗法

• 批准号: 10587020
• 负责人: Zheng David Qian
• 金额: $ 41.65万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587020
• 关键词: Alanine Transaminase; American; Androgens; Animal Model; Antibiotics; Biochemical; Biological; Biology; Biopsy Specimen; CRISPR/Cas technology; Cancer Etiology; Castration; Cell Proliferation; Cell Survival; Cell model; Cessation of life; Clinical; Clinical Trials; Cycloserine; Data; Disease; Disease Outcome; Disease Progression; Fatty Acids; Genetic Transcription; Glutamates; Glutamine; Goals; Growth; Human; Immunohistochemistry; In Vitro; Knowledge; Life; Lipids; Malignant neoplasm of prostate; Mediating; Messenger RNA; Metabolic; Metabolism; Metastatic Prostate Cancer; Methods; Molecular; Mus; Oncogenic; Pathway interactions; Patients; Play; Proteins; Resistance; Resistance development; Role; Sampling; Series; Testing; Therapeutic; Tissue Sample; Transaminases; Xenograft procedure; alpha ketoglutarate; androgen sensitive; anti-cancer; candidate marker; castration resistant prostate cancer; clinically relevant; deprivation; enzalutamide; improved; in vivo; inhibitor; lipid biosynthesis; loss of function; men; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; patient subsets; pre-clinical; preclinical efficacy; programs; prostate cancer cell; prostate cancer model; prostate cancer progression; response; single-cell RNA sequencing; targeted treatment; therapy development; therapy resistant; treatment response; treatment strategy; tumor

PROJECT SUMMARY The goal of this proposal is to develop a new mechanism-based therapy to improve the antitumor efficacy and sustainability of enzalutamide. Metastatic prostate cancer (PCa) is the 2nd-leading cause of cancer death in men in the US. Castration resistant PCa (CRPC) is the most common and lethal form of the disease. Effective and life-saving treatment is an unmet need. Recently, the enzalutamide (Enz)-based treatment has shown promising clinical results. However, many patients do not respond or quickly develop resistance. New mechanistic understandings and treatment strategies are urgently needed to improve Enz. In CRISPR/Cas9- based screen, we identified glutamic pyruvate transaminases (GPT) as a novel vulnerability or target, sensitizing CRPC cells to Enz. Clinically, we found that GPT is amplified or upregulated in subsets of patient samples that were significantly associated with Enz-resistance and poor disease outcomes. Biologically, our preliminary studies suggest that GPT confers adaptive response and resistance to Enz by connecting 3 important oncogenic pathways in CRPC – i) unfolded protein response (UPR), ii) glutamine metabolism, and iii) synthesis of fatty acids and lipids (lipogenesis), which is known as the metabolic hallmark of CRPC and essential to PCa cell survival and proliferation. Therapeutically, we screened a panel of transaminase inhibitors and identified D-cycloserine (DCS), a clinically-approved antibiotic, as a specific and selective inhibitor to GPT, but not other transaminases. Based on these data, we will develop a new therapy approach to improve the antitumor efficacy and sustainability of Enz by targeting GPT with DCS. The central hypothesis is that GPT is a novel molecular vulnerability to PCa cells, especially CRPC, in Enz-based treatments; therefore, GPT can be therapeutically exploited by DCS to improve the efficacy and durability of Enz. We will test the hypothesis in 3 aims. Aim 1 is to understand the mechanisms defining GPT as a novel therapeutic vulnerability to sensitize Enz. We will reveal the biology, explaining why inhibiting GPT improves Enz. Aim 2 is to test the role of GPT-inhibitor DCS to improve Enz in vitro and in vivo. We will test a working hypothesis that DCS sensitizes PCa cells/tumors to Enz by arresting the growth of CRPC tumors and blocking the progression of ADPC tumors to CRPC. Aim 3 is to determine the relevance and significance of GPT in clinical progressions of PCa. We will use immunohistochemistry and single-cell RNA-sequencing to analyze PCa tissues and biopsy samples from patients undergoing Enz-treatments. We will test a working hypothesis that GPT mRNA/proteins are associated with CRPC progression and Enz-resistance.

项目摘要 本研究的目的是开发一种新的基于机制的治疗方法，以提高抗肿瘤疗效 和Enzalutamide的可持续性。转移性前列腺癌（PCa）是癌症死亡的第二大原因 在美国的男人。去势抵抗性前列腺癌（CRPC）是最常见和致命的形式的疾病。 有效和拯救生命的治疗是一个未得到满足的需求。最近，基于恩杂鲁胺（Enz）的治疗已经 显示出良好的临床效果。然而，许多患者没有反应或很快产生耐药性。新 迫切需要机械的理解和治疗策略，以改善恩智浦。在CRISPR/Cas9中- 基于筛选，我们将谷氨酸丙酮酸转移酶（GPT）确定为一种新的脆弱性或靶点， 使CRPC细胞对Enz.在临床上，我们发现GPT在患者的亚群中扩增或上调， 这些样本与Enz-resistance和较差的疾病结果显著相关。从生物学上讲，我们 初步研究表明，GPT通过连接3个 CRPC中的重要致癌途径- i）未折叠蛋白反应（UPR），ii）谷氨酰胺代谢，和iii） 脂肪酸和脂质的合成（脂肪生成），这是CRPC的代谢标志， 对PCa细胞存活和增殖至关重要。在治疗上，我们筛选了一组转氨酶抑制剂 并鉴定了临床批准的抗生素D-环丝氨酸（DCS）作为GPT的特异性和选择性抑制剂， 而不是其它转氨酶。基于这些数据，我们将开发一种新的治疗方法，以改善 通过DCS靶向GPT，增强Enz的抗肿瘤功效和可持续性。核心假设是GPT是一种 在基于酶的治疗中，新的分子对PCa细胞的易感性，特别是CRPC;因此，GPT 可以被DCS用于治疗，以提高Enz的疗效和耐久性。我们将测试 三个目标的假设。目的1是了解GPT作为一种新的治疗脆弱性的机制 让恩兹敏感起来我们将揭示生物学，解释为什么抑制GPT可以改善Enz。目标2是测试 GPT抑制剂DCS在体外和体内改善Enz的作用。我们将测试一个工作假设， 通过阻止CRPC肿瘤的生长和阻断PCa细胞/肿瘤的进展， ADPC肿瘤到CRPC。目的3是确定GPT在临床进展中的相关性和重要性 PCa。我们将使用免疫组织化学和单细胞RNA测序来分析PCa组织和活检组织 来自接受Enz-treatment的患者的样本。我们将测试一个工作假设，即GPT mRNA/蛋白质 与CRPC进展和酶耐药性相关。