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

基本信息

  • 批准号:
    10661960
  • 负责人:
  • 金额:
    $ 21.92万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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 这是一个为期五年的职业发展计划的建议,以研究代谢决定的代谢 作为前列腺癌治疗靶点的方案。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基础上, 临床经验,并整合了她的导师,博士塞缪尔Denmeade和博士两个不同的专业领域。 Erika皮尔斯,了解前列腺癌中高剂量雄激素诱导的代谢脆弱性。尽管 前列腺癌治疗的最新进展,这种疾病继续杀死超过350,000 每年全球男性。标准治疗抑制雄激素受体(AR)信号传导,这通常导致 AR的适应性上调以驱动阻力。我们已经表明,这种AR的上调构成了一种新的免疫调节机制。 易受高剂量雄激素的影响,并正在开发一种称为双极雄激素治疗(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循环, 适应高或低水平的雄激素。迄今为止,我们的临床试验表明,BAT是安全的, 生活质量,并且可以在治疗非常有限的患者亚组中诱导反应 选项.我们现在正在寻求通过识别代谢紊乱来扩大受益于BAT的患者人群。 在最佳可得技术的初始阶段,暴露于高水平的雄激素会导致合成致命的脆弱性。这 该提案的重点是确定代谢的脆弱性,因为(1)雄激素的基本作用, 身体中的许多组织,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的抗性的新兴的共同途径。我们的初步数据 使用全球代谢组学和以代谢为重点的CRISPR基因筛选表明,高剂量 雄激素显著地重新编程前列腺癌代谢,导致脆弱性,包括从头 多胺合成和核苷酸合成。提出的具体目标将询问高合成杀伤力 剂量雄激素与抑制多胺合成(目的1)和抑制核苷酸 合成(目标2)。目标3将评估联合治疗在一组高度表征的 去势抵抗性前列腺癌的患者来源的异种移植物模型,其接近患者的多样性 与这种疾病。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,使她能够过渡到独立作为一个医生科学家,并确定 用于治疗去势抵抗性前列腺癌患者的有前景的组合疗法。

项目成果

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Laura A. Sena其他文献

Intratumoral heterogeneity drives acquired therapy resistance in a patient with metastatic prostate cancer
肿瘤内异质性驱动转移性前列腺癌患者获得性治疗耐药
  • DOI:
    10.1038/s41698-024-00773-w
  • 发表时间:
    2024-12-02
  • 期刊:
  • 影响因子:
    8.000
  • 作者:
    Dena P. Rhinehart;Jiaying Lai;David E. Sanin;Varsha Vakkala;Adrianna Mendes;Christopher Bailey;Emmanuel S. Antonarakis;Channing J. Paller;Xiaojun Wu;Tamara L. Lotan;Rachel Karchin;Laura A. Sena
  • 通讯作者:
    Laura A. Sena
Prostate cancer androgen receptor activity dictates efficacy of Bipolar Androgen Therapy
前列腺癌雄激素受体活性决定双极雄激素治疗的功效
  • DOI:
    10.1101/2022.04.26.22274275
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    20.3
  • 作者:
    Laura A. Sena;Raj Kumar;David E Sanin;Elizabeth A. Thompson;D. M. Rosen;Susan Dalrymple;L. Antony;Yuhan Yang;Carolina Gomes;J. Hicks;T. Jones;Kiara A. Bowers;Jillian N. Eskra;J. Meyers;Anuj Gupta;Alyza M. Skaist;S. Yegnasubramanian;Jun Luo;W. Brennen;S. Kachhap;E. Antonarakis;A. D. De Marzo;J. Isaacs;M. Markowski;S. Denmeade
  • 通讯作者:
    S. Denmeade
Updated analyses for RESTORE cohort C: A trial of bipolar androgen therapy for patients with newly castration-resistant prostate cancer.
RESTORE 队列 C 的更新分析:针对新近去势抵抗性前列腺癌患者的双相雄激素治疗试验。
  • DOI:
    10.1016/j.ejca.2022.12.001
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    8.4
  • 作者:
    Laura A. Sena;Ting Wang;Hao Wang;M. Markowski;E. Antonarakis;S. Denmeade
  • 通讯作者:
    S. Denmeade
The testosterone paradox of advanced prostate cancer: mechanistic insights and clinical implications
晚期前列腺癌的睾酮悖论:机制见解和临床意义
  • DOI:
    10.1038/s41585-022-00686-y
  • 发表时间:
    2022-12-21
  • 期刊:
  • 影响因子:
    14.600
  • 作者:
    Rajendra Kumar;Laura A. Sena;Samuel R. Denmeade;Sushant Kachhap
  • 通讯作者:
    Sushant Kachhap

Laura A. Sena的其他文献

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{{ truncateString('Laura A. Sena', 18)}}的其他基金

The role of mitochondrial metabolism in T cell activation by particulate matter
线粒体代谢在颗粒物激活 T 细胞中的作用
  • 批准号:
    8417009
  • 财政年份:
    2011
  • 资助金额:
    $ 21.92万
  • 项目类别:
The role of mitochondrial metabolism in T cell activation by particulate matter
线粒体代谢在颗粒物激活 T 细胞中的作用
  • 批准号:
    8217316
  • 财政年份:
    2011
  • 资助金额:
    $ 21.92万
  • 项目类别:
The role of mitochondrial metabolism in T cell activation by particulate matter
线粒体代谢在颗粒物激活 T 细胞中的作用
  • 批准号:
    8061140
  • 财政年份:
    2011
  • 资助金额:
    $ 21.92万
  • 项目类别:

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Prostate Specific Anti-androgen Therapy for Localized Prostate Cancer
前列腺特异性抗雄激素疗法治疗局限性前列腺癌
  • 批准号:
    10760194
  • 财政年份:
    2023
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The Role of Myeloid-Derived Suppressor Cells in Resistance to Bipolar Androgen Therapy in Patients with Advanced Prostate Cancer
骨髓源性抑制细胞在晚期前列腺癌患者双极雄激素治疗耐药中的作用
  • 批准号:
    10648749
  • 财政年份:
    2023
  • 资助金额:
    $ 21.92万
  • 项目类别:
Giving prostate cancer enough rope with bipolar androgen therapy
通过双极雄激素治疗为前列腺癌提供足够的支持
  • 批准号:
    nhmrc : GNT1156570
  • 财政年份:
    2019
  • 资助金额:
    $ 21.92万
  • 项目类别:
    Project Grants
Bipolar Androgen Therapy for Progressive Castrate Resistant Prostate Cancer
双极雄激素治疗进行性去势抵抗性前列腺癌
  • 批准号:
    8669473
  • 财政年份:
    2014
  • 资助金额:
    $ 21.92万
  • 项目类别:
Bipolar Androgen Therapy for Progressive Castrate Resistant Prostate Cancer
双极雄激素治疗进行性去势抵抗性前列腺癌
  • 批准号:
    9262192
  • 财政年份:
    2014
  • 资助金额:
    $ 21.92万
  • 项目类别:
INVESTIGATOR INITIATED STUDY OF THE EFFECTS OF ANDROGEN THERAPY ON CARBOHYDRA
研究人员开始研究雄激素治疗对碳水化合物的影响
  • 批准号:
    7982111
  • 财政年份:
    2008
  • 资助金额:
    $ 21.92万
  • 项目类别:
INVESTIGATOR INITIATED STUDY OF THE EFFECTS OF ANDROGEN THERAPY ON CARBOHYDRA
研究人员开始研究雄激素治疗对碳水化合物的影响
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    7716707
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    2008
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    $ 21.92万
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A DIAGNOSTIC TEST TO ASSESS RISK ASSOCIATED WITH ANDROGEN THERAPY
评估雄激素治疗相关风险的诊断测试
  • 批准号:
    7275897
  • 财政年份:
    2007
  • 资助金额:
    $ 21.92万
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INVESTIGATOR INITIATED STUDY OF THE EFFECTS OF ANDROGEN THERAPY ON CARBOHYDRA
研究人员开始研究雄激素治疗对碳水化合物的影响
  • 批准号:
    7603931
  • 财政年份:
    2006
  • 资助金额:
    $ 21.92万
  • 项目类别:
Elucidation of the mechanisms for the growth of androgen-dependent prostate cancer in bone under anti-androgen therapy.
阐明抗雄激素治疗下雄激素依赖性前列腺癌在骨中生长的机制。
  • 批准号:
    18590389
  • 财政年份:
    2006
  • 资助金额:
    $ 21.92万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
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