Synthetic lethal metabolic drug combinations for castration-resistant prostate cancer

治疗去势抵抗性前列腺癌的合成致死代谢药物组合

• 批准号: 10661960
• 负责人: Laura A. Sena
• 金额: $ 21.92万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661960
• 关键词: Androgen Receptor; Androgen Therapy; Androgens; Area; Automobile Driving; Benign; Biological; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; DL-alpha-Difluoromethylornithine; Data; Dependence; Development; Disease; Dose; Down-Regulation; Drug Combinations; Enzymes; Exposure to; Genes; Genetic Screening; Goals; Growth; Hormonal; Immune Tolerance; In Vitro; Malignant - descriptor; Malignant neoplasm of prostate; Mentors; Metabolic; Metabolic Pathway; Metabolism; Modeling; Nucleotide Synthesis Inhibition; Oncology; Ornithine Decarboxylase; Pathway interactions; Patient-Focused Outcomes; Patients; Phase; Physicians; Polyamine Synthesis Inhibition; Polyamines; Program Development; Prostate; Prostate Cancer therapy; Purine Nucleotides; Pyrimidine Nucleotides; Quality of life; Receptor Signaling; Research; Resistance; Scientist; Serum; Signal Transduction; Testing; Testosterone; Therapeutic; Tissues; Training; Treatment Efficacy; Universities; Up-Regulation; Vertebral column; cancer cell; cancer therapy; career development; castration resistant prostate cancer; effective therapy; efficacy evaluation; experience; financial toxicity; improved; improved outcome; in vivo; instructor; medical schools; men; metabolomics; novel therapeutics; nucleotide metabolism; patient derived xenograft model; patient population; patient subsets; programs; prostate cancer cell line; research and development; response; skills; standard of care; targeted treatment; therapeutic target; therapy development; therapy resistant; translational physician; tumor; tumor metabolism

PROJECT SUMMARY This is a proposal for a five-year career development program to study hormonally-determined metabolic programs as therapeutic targets for prostate cancer. The candidate is currently an Instructor of Oncology at Johns Hopkins University School of Medicine. The proposal builds on the candidate’s previous research and clinical experience and integrates two distinct areas of expertise of her mentors, Dr. Samuel Denmeade and Dr. Erika Pearce, to understand metabolic vulnerabilities induced by high dose androgen in prostate cancer. In spite of recent advances in prostate cancer therapy development, this disease continues to kill more than 350,000 men per year worldwide. Standard-of-care therapies inhibit androgen receptor (AR) signaling, which often leads to adaptive upregulation of AR to drive resistance. We have shown that this upregulation of AR constitutes a vulnerability to high dose androgen and are developing a novel therapy called Bipolar Androgen Therapy (BAT) in which high dose androgen is provided intermittently to result in cycling of serum androgens to minimize adaptations to high or low levels of androgens. To date, our clinical trials indicate that BAT is safe, improves quality of life, and can induce responses in a subset of patients for whom there are very limited therapeutic options. We are now seeking to expand the population of patients who benefit from BAT by identifying metabolic synthetic lethal vulnerabilities induced by exposure to high levels of androgens in the initial phase of BAT. This proposal focuses on identifying metabolic vulnerabilities because (1) a fundamental effect of androgens across numerous tissues in the body, including benign and malignant prostate, is alteration of cellular metabolism and (2) metabolic plasticity is an emerging common pathway of resistance to cancer therapies. Our preliminary data using global metabolomics and a metabolism-focused CRISPR-based genetic screen indicate that high dose androgen dramatically reprograms prostate cancer metabolism resulting in vulnerabilities including de novo polyamine synthesis and nucleotide synthesis. Specific aims proposed will interrogate synthetic lethality of high dose androgen in combination with inhibition of polyamine synthesis (Aim 1) and with inhibition of nucleotide synthesis (Aim 2). Aim 3 will assess efficacy of combination therapies across a highly characterized panel of patient-derived xenograft models of castration-resistant prostate cancer that approximate the diversity of patients with this disease. The outlined career development and research plan will provide the candidate with unique cross-disciplinary skills that will enable her transition to independence as a physician scientist and identify promising combination therapies for treatment of patients with castration-resistant prostate cancer.

项目摘要 这是一项为期五年的职业发展计划的建议，用于研究荷尔蒙定代谢 作为前列腺癌的治疗靶标的计划。候选人目前是肿瘤学讲师 约翰·霍普金斯大学医学院。该提案建立在候选人以前的研究和 临床经验并整合了她的导师塞缪尔·丹迈德（Samuel Denmeade）和博士的两个不同专业知识领域 埃里卡·皮尔斯（Erika Pearce），了解前列腺癌中高剂量雄激素引起的代谢脆弱性。以恶意 在前列腺癌疗法开发的最新进展中，这种疾病继续杀死超过350,000 全球男性。护理标准疗法抑制雄激素受体（AR）信号，通常导致 适应AR的上调以驱动电阻。我们已经表明，AR的这种上调构成了 高剂量雄激素的脆弱性，正在开发一种称为双极雄激素疗法（BAT）的新型疗法 其中提供高剂量的雄激素，以使血清雄激素循环以最小化 适应高水平或低水平的雄激素。迄今为止，我们的临床试验表明蝙蝠是安全的，改进了 生活质量，可以在一部分患者中引起反应 选项。我们现在正在寻求通过识别代谢来扩大从蝙蝠中受益的患者人群 在BAT的初始阶段暴露于高水平的雄激素引起的合成致命脆弱性。这 提案重点是确定代谢脆弱性，因为（1）雄激素的基本效果 体内许多组织，包括良性和恶性前列腺，是细胞代谢的改变， （2）代谢可塑性是对癌症疗法抗性的新兴途径。我们的初步数据 使用全球代谢组学和基于代谢的CRISPR遗传筛选，表明高剂量 雄激素急剧重新编程前列腺癌代谢，导致脆弱性，包括从头开始 多胺合成和核苷酸合成。提出的具体目的将审问高的合成致死性 剂量雄激素与抑制多胺合成（AIM 1）和抑制核苷酸联合剂量 合成（目标2）。 AIM 3将评估组合疗法的效率 耐castration-耐药前列腺癌的患者衍生的特征模型近似患者的多样性 有这种疾病。概述的职业发展和研究计划将为候选人提供独特的 跨学科的技能将使她能够过渡到独立作为物理科学家并确定 有希望的联合疗法用于治疗cast割的前列腺癌患者。