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
基本信息
- 批准号:10372921
- 负责人:
- 金额:$ 37.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:AR geneAllelesAndrogen MetabolismAndrogen ReceptorAndrogensBiological MarkersCYP17A1 geneCastrationClinicalClinical DataClinical ManagementClinical ResearchClinical TrialsDevelopmentDiseaseEnzymesGenerationsGenetic PolymorphismGoalsGrowthHydroxysteroid DehydrogenasesInheritedMalignant NeoplasmsMalignant neoplasm of prostateMedical CastrationMetabolicMetabolismMetastatic Prostate CancerNeoadjuvant TherapyNeoplasm MetastasisPatient CarePatient-Focused OutcomesPatientsPharmaceutical PreparationsPhase III Clinical TrialsPredispositionProstate Cancer therapyPublishingReceptor SignalingResistanceResistance developmentSignal TransductionStanoloneSteroidsTestosteroneTimeTissuesVariantWorkadvanced prostate canceradverse outcomeandrogen deprivation therapyantagonistbiomarker performancecastration resistant prostate cancerclinical practicecohortdocetaxelgain of functiongenetic varianthormone therapyimproved outcomeinhibitormolecular markernovelpatient responsepredictive markerresponseresponse biomarkerstandard of caresteroid metabolismtreatment durationtumor
项目摘要
Project Summary
Prostate cancer depends on androgens and the androgen receptor (AR) for growth and progression.
Metastatic tumors are usually initially treated with androgen deprivation therapy (ADT) by way of medical or
surgical castration; however, tumors eventually recur as castration-resistant prostate cancer (CRPC), which
progresses due to the intratumoral generation of testosterone and/or dihydrotestosterone (DHT) and AR
stimulation. The intratumoral synthesis of potent androgens requires the activity of steroidogenic enzymes. In
the prior project period, we identified the first example of a gain-of-function missense in a steroidogenic enzyme
that increases what is otherwise the rate-limiting step of DHT synthesis from extragonadal precursor steroids and
spurs the development of CRPC. This missense in 3β-hydroxysteroid dehydrogenase-1 (3βHSD1) is encoded by
HSD3B1(1245C), a common germline variant. In the prior project period, we also discovered that patients with
advanced prostate cancer who inherit the HSD3B1(1245C) genetic variant and receive ADT progress to CRPC
more rapidly than patients who inherit the wild-type HSD3B1 enzyme, which has lower activity. Although
clinical data across 4 patient cohorts now show that the HSD3B1(1245C) genetic variant is a predictive biomarker
of resistance to ADT, the precise clinical utility of this biomarker remains uncertain. The overarching goal of
this proposal is to determine how HSD3B1(1245C) should be utilized as a biomarker to identify patients who
require more intensive upfront treatment and who are otherwise likely to progress more rapidly to lethal disease.
As the HSD3B1(1245C) variant encodes for an enzyme that enables more rapid conversion of
extragonadal precursors to DHT, we hypothesize that HSD3B1(1245C) is a predictive biomarker of sensitivity to
drugs that block the synthesis or effects extragonadal androgens. We hypothesize that metabolism by 3βHSD1
is a class effect of steroidal CYP17A1 inhibitors, thus making non-steroidal CYP17A1 inhibitors or potent AR
antagonists more suitable for treating patients who harbor the HSD3B1(1245C) variant. Finally, we hypothesize
that intensification of treatment at the time of ADT in phase III clinical trials improves outcomes for patients with
metastatic prostate cancer who inherit the HSD3B1(1245C) variant. In Aim 1, we will determine if inheritance
of the HSD3B1(1245C) variant is a predictive biomarker of response to non-steroidal CYP17A1 inhibitors or
potent AR antagonists. In Aim 2, we will identify whether susceptibility to 3βHSD metabolism is a class effect
of steroidal CYP17A1 inhibitors and how this may determine response for patients who inherit the HSD3B1
variant. In Aim 3, we will determine if patients with prostate cancer who inherit the HSD3B1(1245C) variant
specifically benefit from more intensive upfront treatment at the time of ADT. If we are correct, the work in this
proposal will change standard clinical practice for the treatment of prostate cancer.
项目总结
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)
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Nima Sharifi其他文献
Nima Sharifi的其他文献
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{{ 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:
10557156 - 财政年份:2022
- 资助金额:
$ 37.47万 - 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:
10442233 - 财政年份:2022
- 资助金额:
$ 37.47万 - 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:
$ 37.47万 - 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:
$ 37.47万 - 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:
$ 37.47万 - 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:
$ 37.47万 - 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:
$ 37.47万 - 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:
$ 37.47万 - 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:
$ 37.47万 - 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:
$ 37.47万 - 项目类别:
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