CYP17A1-independent androgen synthesis and prostate cancer resistance to next-generation hormonal therapy
CYP17A1独立的雄激素合成和前列腺癌对下一代激素治疗的抵抗
基本信息
- 批准号:10557156
- 负责人:
- 金额:$ 6.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2023-06-09
- 项目状态:已结题
- 来源:
- 关键词:Adrenal GlandsAndrogen ReceptorAndrogensAntiandrogen TherapyBindingBiochemical PathwayBypassCYP17A1 geneCancer EtiologyCastrationCell NucleusCessation of lifeCholesterolClinical DataClinical ResearchDataDetectionDiscriminationDiseaseDrug resistanceEnzymesGenerationsGoalsHormonalHydroxysteroid DehydrogenasesHyperactivityMalignant neoplasm of prostateMapsMass Spectrum AnalysisMedical CastrationMedical GeneticsMetabolicMethodologyMethodsModelingNatural regenerationPathway interactionsPatientsPhosphorylationPhosphorylation SitePhysiologicalProstateProstate Cancer therapyResistanceResistance developmentRoleSerumStanoloneSteroid biosynthesisSteroidsTestisTestosteroneWorkabirateroneadvanced prostate cancerandrogen biosynthesisandrogen deprivation therapyantagonistcastration resistant prostate cancercell growthdocetaxelenzalutamideenzyme activityhormone therapyinhibitorinnovationintratumoral androgenionizationmenneoplastic cellnew therapeutic targetnext generationnovelpharmacologicphase III trialtherapy resistanttumor
项目摘要
Summary
Androgen deprivation therapy (ADT), with medical or surgical castration, is the long-standing frontline treatment
for advanced prostate cancer. Phase 3 trials show a profound survival benefit for addition of 1 of 4 agents
(abiraterone, docetaxel, enzalutamide or apalutamide) to intensify treatment with ADT. Unfortunately, drug
resistance eventually occurs, and disease almost always progresses as lethal castration-resistant prostate
cancer (CRPC). Regeneration of potent androgens that stimulate the androgen receptor (AR) is a major driver
of resistance, as is evidenced by the survival benefit conferred by blocking androgen synthesis (e.g., CYP17A1
inhibition) or directly blocking AR with potent antagonists. 5α-dihydrotestosterone (DHT) is the major androgen
that binds AR, and clinical studies of CRPC have consistently shown that intratumoral DHT is elevated to
physiologically relevant levels. Genetic clinical evidence now demonstrates a clear role for 3β-hydroxysteroid
dehydrogenase-1 (3βHSD1) in treatment resistance. The regeneration of DHT during ADT is due to intratumoral
androgen synthesis from precursors that may originate via de novo steroidogenesis from cholesterol or utilization
of adrenal precursor steroids. There are at least 3 possible pathways to DHT synthesis which all require
CYP17A1 - the pharmacologic target of abiraterone. No biochemical pathway of androgen synthesis is
known to circumvent this requirement for CYP17A1. Further, all pathways for the synthesis of
testosterone (T) and/or DHT require 3βHSD enzymatic activity. Clinical data from > 800 patients showing
that a genetically hyperactive form of 3βHSD1 is associated with resistance to CYP17A1 inhibition led us to
pursue the possibility that a CYP17A1-independent pathway exists that bypasses next-generation hormonal
therapy blockade. We have identified an oxysterol that prostate cancer uses as a substrate for androgen
generation via a pathway that is impervious to CYP17A1 inhibition. In contrast, this same pathway is
blocked by 3βHSD1 inhibition. Our further data suggest that 3βHSD1 phosphorylation is absolutely essential for
enzymatic activation. We propose to determine the role of alternative steroidogenesis pathways that utilize
3βHSD1, thus circumventing the requirement for CYP17A1 and enabling resistance to next-generation hormonal
therapies. We will determine the role of CYP17A1-independent androgen synthesis in next-generation anti-
androgen therapy resistance. Furthermore, we will identify and exploit phosphorylation sites that are required for
3βHSD1-dependent and CYP17A1-independent androgen synthesis. Impact: Prostate cancer is the second
leading cause of cancer death in U.S. men. Our studies will pave the way to mapping out an entirely new
biochemical pathway of androgen synthesis that will define a major mechanism of treatment resistance and new
targets for therapy. Our work is highly innovative because this pathway is entirely novel, and we will identify
precursor metabolites for androgen synthesis using an approach that, to our knowledge, has not previously been
utilized for this purpose.
总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Nima Sharifi其他文献
Nima Sharifi的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Nima Sharifi', 18)}}的其他基金
CYP17A1-independent androgen synthesis and prostate cancer resistance to next-generation hormonal therapy
CYP17A1独立的雄激素合成和前列腺癌对下一代激素治疗的抵抗
- 批准号:
10442233 - 财政年份:2022
- 资助金额:
$ 6.38万 - 项目类别:
CYP17A1-independent androgen synthesis and prostate cancer resistance to next-generation hormonal therapy
CYP17A1独立的雄激素合成和前列腺癌对下一代激素治疗的抵抗
- 批准号:
10842022 - 财政年份:2022
- 资助金额:
$ 6.38万 - 项目类别:
Aberrant tumor metabolism that enables AR antagonist-resistant prostate cancer
肿瘤代谢异常导致 AR 拮抗剂耐药前列腺癌
- 批准号:
9886389 - 财政年份:2019
- 资助金额:
$ 6.38万 - 项目类别:
Aberrant tumor metabolism that enables AR antagonist-resistant prostate cancer
异常的肿瘤代谢导致 AR 拮抗剂对前列腺癌产生耐药性
- 批准号:
10847199 - 财政年份:2019
- 资助金额:
$ 6.38万 - 项目类别:
Aberrant tumor metabolism that enables AR antagonist-resistant prostate cancer
肿瘤代谢异常导致 AR 拮抗剂耐药前列腺癌
- 批准号:
10058257 - 财政年份:2019
- 资助金额:
$ 6.38万 - 项目类别:
Aberrant tumor metabolism that enables AR antagonist-resistant prostate cancer
肿瘤代谢异常导致 AR 拮抗剂耐药前列腺癌
- 批准号:
10308051 - 财政年份:2019
- 资助金额:
$ 6.38万 - 项目类别:
Aberrant tumor metabolism that enables AR antagonist-resistant prostate cancer
肿瘤代谢异常导致 AR 拮抗剂耐药前列腺癌
- 批准号:
10521260 - 财政年份:2019
- 资助金额:
$ 6.38万 - 项目类别:
Elucidating a novel molecular biomarker for castration-resistant prostate cancer
阐明去势抵抗性前列腺癌的新型分子生物标志物
- 批准号:
10113548 - 财政年份:2018
- 资助金额:
$ 6.38万 - 项目类别:
Elucidating a novel molecular biomarker for castration-resistant prostate cancer
阐明去势抵抗性前列腺癌的新型分子生物标志物
- 批准号:
10372921 - 财政年份:2018
- 资助金额:
$ 6.38万 - 项目类别:
Elucidating a novel molecular biomarker for castration-resistant prostate cancer
阐明去势抵抗性前列腺癌的新型分子生物标志物
- 批准号:
9900724 - 财政年份:2018
- 资助金额:
$ 6.38万 - 项目类别:
相似海外基金
Androgen receptor: A master regulator of lipid metabolism
雄激素受体:脂质代谢的主要调节因子
- 批准号:
DP230103210 - 财政年份:2023
- 资助金额:
$ 6.38万 - 项目类别:
Discovery Projects
Regulation of androgen receptor signaling in prostate cancer by protein arginine methylation
通过蛋白质精氨酸甲基化调节前列腺癌中的雄激素受体信号传导
- 批准号:
10584689 - 财政年份:2023
- 资助金额:
$ 6.38万 - 项目类别:
Structural and functional analysis of a novel class of androgen receptor antagonists
一类新型雄激素受体拮抗剂的结构和功能分析
- 批准号:
10650956 - 财政年份:2023
- 资助金额:
$ 6.38万 - 项目类别:
Role of the Androgen Receptor in Insulin Secretion in the Male
雄激素受体在男性胰岛素分泌中的作用
- 批准号:
10488954 - 财政年份:2023
- 资助金额:
$ 6.38万 - 项目类别:
Targeting tumor cell macrophage lipid interactions to overcome resistance to androgen receptor targeted therapy
靶向肿瘤细胞巨噬细胞脂质相互作用以克服对雄激素受体靶向治疗的耐药性
- 批准号:
10651105 - 财政年份:2023
- 资助金额:
$ 6.38万 - 项目类别:
Preclinical development of ONCT-505, an Androgen Receptor Antagonist and Degrader, as new potential therapeutic for Kennedy's Disease
ONCT-505(一种雄激素受体拮抗剂和降解剂)的临床前开发,作为肯尼迪病的新潜在治疗方法
- 批准号:
10603636 - 财政年份:2023
- 资助金额:
$ 6.38万 - 项目类别:
Proliferating cell nuclear antigen in regulation of androgen receptor signalings in castration-resistant prostate cancer cells
增殖细胞核抗原对去势抵抗性前列腺癌细胞雄激素受体信号传导的调节
- 批准号:
10544062 - 财政年份:2022
- 资助金额:
$ 6.38万 - 项目类别:
Effects of androgen receptor (AR) signaling on CD4+ T cell metabolism during airway inflammation
气道炎症期间雄激素受体 (AR) 信号对 CD4 T 细胞代谢的影响
- 批准号:
10534943 - 财政年份:2022
- 资助金额:
$ 6.38万 - 项目类别:
TITLE: BLADDER CANCER CHEMOPREVENTION USING THE ANDROGEN RECEPTOR INHIBITOR APALUTAMIDE
标题:使用雄激素受体抑制剂阿帕鲁胺进行膀胱癌化学预防
- 批准号:
10677989 - 财政年份:2022
- 资助金额:
$ 6.38万 - 项目类别: