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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：
10640684
负责人：
Nima Sharifi
金额：
$ 42.21万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-26 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640684
关键词：
Ablation Adrenal Glands Adverse effects Alleles Androgens Aromatase Automobile Driving Award BMX gene Bile Acids Biological Markers Biology Cancer Etiology Castrate sensitive prostate cancer Castration Cell Line Cessation of life Clinical Clinical Trials Collaborations DNA Data Disease Enrollment Enzyme Inhibition Enzymes Estrogen receptor positive FDA approved Genetic Genotype Germ-Line Mutation Gonadal Steroid Hormones Hepatic Hepatocyte Human Hydroxysteroid Dehydrogenases Inherited Institution Ketone Bodies Link Malignant Neoplasms Malignant neoplasm of prostate Medical Castration Metabolic Metabolism Modeling Molecular Natural regeneration Nonmetastatic Oncology Outcome Patient Care Patient Selection Patients Pharmaceutical Preparations Phase II Clinical Trials Phosphorylation Phosphotransferases Physiology Postmenopause Prior Therapy Process Prostate Cancer therapy Reproducibility Research Personnel Resistance Role Sampling Selection for Treatments Serum Signal Transduction Stanolone Steroids Testing Therapeutic Tumor Biology Variant Work abiraterone advanced prostate cancer androgen biosynthesis androgen deprivation therapy base castration resistant prostate cancer clinically significant dehydroepiandrosterone design efficacy evaluation gain of function genetic variant hormone therapy improved in vivo individual patient innovation ketogenesis liver metabolism malignant breast neoplasm men molecular marker novel permissiveness pharmacologic predictive marker standard of care steroid metabolism treatment choice tumor tumor growth

项目摘要

SUMMARY Prostate cancer is the second leading cause of cancer death in U.S. men. The frontline treatment for advanced prostate cancer is androgen deprivation therapy (ADT), which has been the standard of care for ~80 years. Recent practice-changing data have demonstrated a survival benefit when ADT is intensified, but the treatment choice for intensification is unclear. Regardless, metastatic disease almost always progresses as castration-resistant prostate cancer (CRPC). A major limitation of new CRPC treatments is that patients are selected based on prior therapies instead of their genetics and disease-driving molecular processes. Essential findings from our previous project period include clear and reproducible clinical evidence that an “adrenal-permissive” HSD3B1(1245C) germline variant encodes for a gain-of-function missense in 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), the rate-limiting steroidogenic enzyme for synthesis of 5α-dihydrotestosterone (DHT) from extragonadal precursor steroids. This adrenal-permissive HSD3B1 is a genetic and metabolic driver of hormone therapy resistance. In this renewal application, we propose to determine the mechanisms and clinical significance of inheritance of the HSD3B1(1245C) variant and move toward its use as a biomarker to tailor castration- resistant and castration-sensitive prostate cancer treatment to the individual patient's genetics and tumor biology. We hypothesize that the germline HSD3B1(1245C) variant is a predictive biomarker that will allow us to identify patients who will benefit from upfront adrenal androgen ablation. Our preliminary data indicate that BMX inhibition of 3βHSD1 phosphorylation will be therapeutic – direct therapeutic inhibition of 3βHSD1 for men with the adrenal-permissive HSD3B1 should reverse the adverse biology and clinical outcomes conferred by extragonadal androgen biosynthesis in CRPC. Our data also indicate that after intensified hormonal therapy, HSD3B1 inheritance is a determinant of systemic metabolic effects, including adverse effects seen in some men, but not others. The potential clinical consequences of the concepts we propose are profound because they couple a germline disease-driving metabolic driver to therapeutic mechanisms for reversal of poor outcomes. Aim 1: Determine whether inheritance of the adrenal-permissive HSD3B1(1245C) allele is a predictive biomarker of improved benefit from adding abiraterone to ADT for non-metastatic castration-sensitive prostate cancer. We will analyze germline DNA available from 959 men enrolled in the STAMPEDE trial. Aim 2: Define the role of phosphorylation in 3βHSD1 activation and determine the role of BMX in the conversion of DHEA to downstream potent androgens. We will determine if the BMX kinase is essential for 3βHSD1 phosphorylation and cellular activation and test its efficacy in a proof-of-concept clinical trial. Aim 3: Determine the mechanistic link between HSD3B1 inheritance and circulating metabolites in men undergoing intensive hormonal therapy. The mechanisms that regulate these circulating metabolites are most likely a function of hepatic metabolism, so we will test whether the effects of HSD3B1 genotype occur via sex steroid signaling or bile acid signaling.

总结前列腺癌是美国男性癌症死亡的第二大原因。晚期癌症的一线治疗前列腺癌的治疗方法是雄激素剥夺疗法（ADT），其已经成为护理标准约80年。最近实践改变的数据已经证明，当ADT强化时，强化的原因尚不清楚。无论如何，转移性疾病几乎总是进展为去势抵抗前列腺癌（CRPC）。新的CRPC治疗的主要限制是基于先前的CRPC治疗选择患者。治疗，而不是他们的遗传和疾病驱动的分子过程。我们之前的主要发现项目期间包括明确和可重现的临床证据，表明“肾上腺允许”HSD 3B 1（1245 C）种系变体编码3β-羟基类固醇脱氢酶-1（3β HSD 1）的功能获得性错义，性腺外合成5α-二氢睾酮限速酶类固醇前体这种肾上腺允许的HSD 3B 1是激素治疗的遗传和代谢驱动因素阻力在这次更新申请中，我们建议确定 HSD 3B 1（1245 C）变异体的遗传，并将其用作定制去势的生物标志物- 对个体患者的遗传学和肿瘤具有抗性和去势敏感性的前列腺癌治疗生物学我们假设生殖系HSD 3B 1（1245 C）变异是一种预测性生物标志物，以确定哪些患者将受益于前期肾上腺雄激素消融。我们的初步数据显示， BMX对3β HSD 1磷酸化的抑制将是治疗性的--直接治疗性抑制3β HSD 1，患有肾上腺允许性HSD 3B 1的男性应该逆转由以下因素引起的不良生物学和临床结果： CRPC中的性腺外雄激素生物合成。我们的数据还表明，在强化激素治疗后， HSD 3B 1遗传是全身代谢影响的决定因素，包括在一些男性中观察到的不良影响，而不是其他人。我们提出的概念的潜在临床后果是深远的，因为它们将生殖系疾病驱动代谢驱动因素与治疗机制结合起来，以逆转不良结局。目的1：确定肾上腺素允许的HSD 3B 1（1245 C）等位基因的遗传是否是一个预测性因素。在ADT基础上添加阿比特龙治疗非转移性去势敏感性前列腺获益改善的生物标志物癌我们将分析959名参加STAMPEDE试验的男性的生殖系DNA。目标2：定义磷酸化在3β HSD 1活化中的作用，并确定BMX在DHEA转化为下游强有力的雄激素。我们将确定BMX激酶是否是3β HSD 1磷酸化所必需的和细胞活化，并在概念验证临床试验中测试其功效。目标3：确定机制在接受强化激素治疗的男性中，HSD 3B 1遗传与循环代谢物之间存在联系。调节这些循环代谢物的机制很可能是肝脏代谢的功能，因此，我们将测试HSD 3B 1基因型的作用是否通过性类固醇信号或胆汁酸信号发生。

项目成果

期刊论文数量（35）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Loss of an Androgen-Inactivating and Isoform-Specific HSD17B4 Splice Form Enables Emergence of Castration-Resistant Prostate Cancer.

DOI：
10.1016/j.celrep.2017.12.081
发表时间：
2018-01-16
期刊：
Cell reports
影响因子：
8.8
作者：
Ko HK;Berk M;Chung YM;Willard B;Bareja R;Rubin M;Sboner A;Sharifi N
通讯作者：
Sharifi N

Development and validation of a novel LC-MS/MS method for simultaneous determination of abiraterone and its seven steroidal metabolites in human serum: Innovation in separation of diastereoisomers without use of a chiral column.

DOI：
10.1016/j.jsbmb.2016.04.002
发表时间：
2017-09
期刊：
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
影响因子：
4.1
作者：
Alyamani, Mohammad;Li, Zhenfei;Upadhyay, Sunil K.;Anderson, David J.;Auchus, Richard J.;Sharifi, Nima
通讯作者：
Sharifi, Nima

Abiraterone acetate treatment lowers 11-oxygenated androgens.