Synthetic lethal metabolic drug combinations for castration-resistant prostate cancer

项目总结 这是一项为期五年的职业发展计划，旨在研究由荷尔蒙决定的新陈代谢。 计划作为前列腺癌的治疗靶点。该候选人目前是一名肿瘤学讲师， 约翰霍普金斯大学医学院。这项提议建立在候选人之前的研究和 临床经验，并整合了她的导师Samuel Denmeade博士和Dr. Erika Pearce，了解高剂量雄激素在前列腺癌中诱导的代谢脆弱性。尽管 在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 全世界每年的男性数量。标准护理疗法抑制雄激素受体(AR)信号传递，这通常导致 自适应上调AR以驱动阻力。我们已经证明，AR的这种上调构成了 对高剂量雄激素的易感性，正在开发一种名为双相雄激素疗法(BAT)的新疗法 其中间歇性地提供高剂量雄激素以导致血清雄激素的循环以使 对高水平或低水平雄激素的适应。到目前为止，我们的临床试验表明BAT是安全的，改善了 生活质量，并可以在治疗方法非常有限的一部分患者中诱导反应 选择。我们现在正在寻求通过确定新陈代谢来扩大从BAT中受益的患者群体 在蝙蝠的初始阶段暴露于高水平的雄激素而导致的合成致死脆弱性。这 该提案侧重于确定新陈代谢的脆弱性，因为(1)雄激素在 体内的许多组织，包括良性和恶性的前列腺，都是细胞代谢的改变和 (2)代谢可塑性是肿瘤治疗抵抗的一种常见途径。我们的初步数据 使用全球代谢组学和以新陈代谢为重点的CRISPR基因筛查表明，高剂量 雄激素大幅重排前列腺癌新陈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。提出的具体目标将审问HIGH的综合致命性 剂量雄激素联合多胺合成抑制(目标1)和核苷酸抑制 综合(目标2)。AIM 3将评估联合疗法的疗效，评估的对象是具有高度特征的 接近患者多样性的抗去势前列腺癌患者来源的异种移植模型 得了这种病。概述的职业发展和研究计划将为应聘者提供独特的 跨学科的技能，使她能够过渡到独立成为一名内科科学家，并确定 用于治疗去势抵抗前列腺癌患者的有希望的联合疗法。

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.