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.

项目概要 这是一项为期五年的职业发展计划的提案，旨在研究激素决定的代谢 该候选人目前是肿瘤学讲师 该提案建立在候选人之前的研究和基础上。 临床经验，并整合了她的导师 Samuel Denmeade 博士和 Dr. Samuel Denmeade 两个不同的专业领域。 Erika Pearce，了解高剂量雄激素在前列腺癌中引起的代谢脆弱性。 前列腺癌治疗发展的最新进展中，这种疾病继续导致超过 350,000 人死亡 每年全世界男性的标准护理疗法会抑制雄激素受体 (AR) 信号，这通常会导致 AR 的适应性上调以驱动耐药性 我们已经证明 AR 的这种上调构成了一种机制。 易受高剂量雄激素影响，正在开发一种称为双极雄激素疗法 (BAT) 的新型疗法 其中间歇性地提供高剂量雄激素以导致血清雄激素循环以最小化 对高或低水平雄激素的适应迄今为止，我们的临床试验表明 BAT 是安全的，并且可以改善。 生活质量，并且可以在治疗非常有限的一小部分患者中引起反应 我们现在正在寻求通过识别代谢来扩大受益于 BAT 的患者群体。 在 BAT 的初始阶段暴露于高水平的雄激素会导致合成致命的脆弱性。 该提案的重点是识别代谢脆弱性，因为（1）雄激素对整个身体的根本影响 体内的许多组织，包括良性和恶性前列腺，正在改变细胞代谢和 (2) 代谢可塑性是一种新兴的癌症治疗耐药途径。 使用全局代谢组学和基于代谢的 CRISPR 基因筛选表明高剂量 雄激素极大地重新编程前列腺癌的代谢，导致包括从头开始在内的脆弱性 多胺合成和核苷酸合成的具体目标将探讨高合成杀伤力。 雄激素剂量与多胺合成抑制（目标 1）和核苷酸抑制相结合 合成（目标 2）将评估一组高度特征化的联合疗法的疗效。 源自患者的去势抵抗性前列腺癌异种移植模型接近患者的多样性 患有这种疾病的职业发展和研究计划将为候选人提供独特的机会。 跨学科技能将使她能够过渡为独立的医师科学家，并确定 用于治疗去势抵抗性前列腺癌患者的有前景的联合疗法。