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 该建议的目的是开发一种基于机制的新疗法来提高抗肿瘤效率 和enzalutamide的可持续性。转移性前列腺癌（PCA）是癌症死亡的第二个领先原因 在美国的男人。耐can割PCA（CRPC）是该疾病的最常见和致命形式。 有效和挽救生命的治疗是未满足的需求。最近，基于enzalutamide（ENZ）的治疗 显示出令人鼓舞的临床结果。但是，许多患者没有反应或迅速产生抗性。新的 迫切需要机械理解和治疗策略来改善ENZ。在crispr/cas9- 基于屏幕，我们确定谷氨酸丙酮酸转氨酶（GPT）是一种新型脆弱性或目标， 将CRPC细胞敏感到ENZ。临床上，我们发现GPT在患者子集中得到了扩增或更新 与ENZ抗性和疾病结果差的样本。生物学上，我们的 初步研究表明，GPT通过连接3承认自适应反应和对ENZ的抵抗力3 CRPC中的重要致癌途径 - i）展开的蛋白质反应（UPR），ii）谷氨酰胺代谢，III） 脂肪酸和脂质（脂肪生成）的合成，这被称为CRPC的代谢标志和 PCA细胞存活和增殖必不可少的。在治疗上，我们筛选了一组转氨酶抑制剂 并确定了D-Cycloserine（DCS），一种临床批准的抗生素，是一种特异性和选择性抑制剂GPT， 但不是其他转氨酶。基于这些数据，我们将开发一种新的疗法来改善 通过用DC靶向GPT，ENZ的抗肿瘤效率和可持续性。中心假设是GPT是 基于ENZ的治疗中，针对PCA细胞，尤其是CRPC的新型分子脆弱性；因此，gpt DC可以热探索以提高ENZ的效率和耐用性。我们将测试 3个目标中的假设。目标1是了解将GPT定义为新型治疗脆弱性的机制 感觉恩。我们将揭示生物学，解释为什么抑制GPT会改善ENZ。目标2是测试 GPT抑制剂DC在体外和体内改善ENZ的作用。我们将测试DCS的工作假设 通过阻止CRPC肿瘤的生长并阻止PCA细胞/肿瘤的ENZ ADPC肿瘤至CRPC。目标3是确定GPT在临床进程中的相关性和意义 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 来自接受ENZ治疗的患者的样本。我们将检验一个gpt mRNA/蛋白质的工作假设 与CRPC的进展和抗性有关。