The MSKCC-UW/Fred Hutch Prostate Cancer Drug Resistance and Sensitivity Center

MSKCC-UW/Fred Hutch 前列腺癌耐药性和敏感性中心

基本信息

批准号：
10250359
负责人：
CHARLES L. SAWYERS
金额：
$ 132.32万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10250359
关键词：
AR gene Address Androgen Receptor Biological Assay Biological Markers Biopsy Blood Bypass Cancer Patient Categories Cessation of life Chromatin Chromatin Remodeling Factor Clinical Clinical Research Clinical Trials Collection Combination Drug Therapy Combined Modality Therapy DNA DNA sequencing Data Data Set Development Disease Dreams Drug Targeting Drug resistance Drug usage EP300 gene ERBB2 gene ERBB3 gene EZH2 gene Ensure FGF8 gene FGF9 gene Fibroblast Growth Factor Receptors Gene Amplification Gene Expression Genomics Glucocorticoid Receptor Goals Heterogeneity Human Immune Individual Intervention Laboratories Link Malignant Neoplasms Malignant neoplasm of prostate Memorial Sloan-Kettering Cancer Center Metastatic Prostate Cancer Microtubules Modeling Mutation Nuclear Hormone Receptors Organoids PI3K/AKT PTEN gene Pathway interactions Patient Selection Patients Pharmaceutical Preparations Phosphotransferases Play Pre-Clinical Model Production Prostate Cancer therapy Proto-Oncogene Proteins c-akt Reagent Receptor Inhibition Receptor Signaling Regimen Repression Resistance Resistance development Role Serum Markers Signal Pathway Signal Transduction TP53 gene Testing Therapeutic Vertebral column Work abiraterone angiogenesis autocrine base biomarker identification cancer drug resistance cancer type castration resistant prostate cancer clinical development clinical translation cohort drug sensitivity hormone therapy improved inhibitor/antagonist insight kinase inhibitor member men molecular marker next generation novel therapeutics patient biomarkers patient derived xenograft model patient response potential biomarker pre-clinical preclinical study prevent programs prostate cancer model prototype resistance mechanism success targeted treatment therapy resistant tumor tumor DNA tumor microenvironment

项目摘要

OVERALL ABSTRACT The lethal stage of metastatic prostate cancer, called castration resistant prostate cancer (CRPC), kills ~26,000 men per year in the US. Despite remarkable improvements in survival with next generation AR pathway inhibitors such as abiraterone and enzalutamide, CRPC patients ultimately progress and die from their disease. Our understanding of the mechanisms of acquired resistance to AR therapy has increased dramatically in recent years, largely based on genomic landscape analyses of tumors from CRPC patients and preclinical studies of acquired resistance in patient-derived models (organoids, PDX). Much of this progress is directly linked to the members of this Drug Resistance and Sensitivity Center (DRSC) team. A major mechanistic insight from these studies is the recognition of two categories of AR therapy resistance: one in which AR pathway signaling is restored and the other in which it remains inhibited. Underlying both categories are a heterogeneous set of resistance mechanisms, many of which were discovered by our DRSC team members. Importantly, we have shown that several of these resistance mechanisms can be targeted with current clinical grade drugs. The overarching goal of this DRSC proposal is to evaluate these translational opportunities across a unique set of preclinical organoid and PDX models (again, discovered and developed by our DRSC team members) and to catalyze the initiation of clinical studies in patients most likely to benefit based on appropriate biomarker profiles. We address this goal in three Projects. Project 1 focuses on resistance caused by restored AR pathway function, which occurs in over ~50% of CRPC patients, by targeting the glucocorticoid receptor, which is upregulated and substitutes for AR, or by further inhibition of AR signaling using drugs targeting specific components of the chromatin machinery. Project 2 will take a similar approach but will focus on the opposite category of acquired resistance (absence of restored AR pathway activity), leveraging insights from our recent data showing that cancer can revert from an AR-negative to AR-positive state by targeting specific chromatin modifiers. Project 3 integrates with Projects 1 and 2 by focusing on kinase inhibitors as an adjunct to AR pathway therapy in two distinct contexts – PI3K/AKT activation in tumors with PTEN loss and FGFR activation in tumors with autocrine FGF8/FGF9 production. Excitingly, a recent clinical trial of combined AKT and AR inhibition, which was initiated based on our earlier work, demonstrated a significant improvement in survival for patients with PTEN loss prostate cancer. The Administrative Core will oversee the integration of the Projects with each other, with NCI scientific staff and with other DRSCs. Collectively our studies will validate various combination therapy regimens, in conjunction with molecular biomarkers for patient selection, as a critical step toward clinical translation. In addition, the drugs and targets studied here are broadly relevant for multiple cancer types.

总体摘要转移性前列腺癌的致死阶段称为去势抵抗性前列腺癌 (CRPC)，可导致死亡尽管下一代 AR 的生存率显着提高，但美国每年约有 26,000 名男性。使用阿比特龙和恩杂鲁胺等途径抑制剂，CRPC 患者最终会进展并死于我们对 AR 疗法获得性耐药机制的了解有所增加。近年来，这在很大程度上基于对 CRPC 患者肿瘤的基因组图谱分析和患者来源模型（类器官、PDX）中获得性耐药的临床前研究大部分进展是在以下方面进行的：与该耐药性和敏感性中心 (DRSC) A 专业团队的成员直接相关。这些研究的机制洞察是认识到 AR 治疗耐药性的两类：一类是哪种 AR 信号通路被恢复，另一种则在这两个类别中仍然受到抑制。是一组异质的耐药机制，其中许多是由我们的 DRSC 团队发现的重要的是，我们已经证明其中一些抵抗机制可以针对其中一些。该 DRSC 提案的首要目标是评估这些转化药物。跨越一组独特的临床前类器官和 PDX 模型的机会（同样，由我们的 DRSC 团队成员）并促进最有可能受益的患者开展临床研究基于适当的生物标志物概况，我们在三个项目中实现了这一目标。 AR 通路功能恢复引起的耐药性，这种情况发生在超过 50% 的 CRPC 患者中，通过靶向糖皮质激素受体，其上调并替代 AR，或通过进一步抑制 AR 信号传导使用针对染色质机制特定成分的药物，项目 2 将采取类似的方法。但将重点关注相反类别的获得性耐药（缺乏恢复的 AR 途径活性），利用我们最新数据的见解，表明癌症可以从 AR 阴性恢复为 AR 阳性通过针对特定的染色质修饰剂来说明项目 3 通过关注项目 1 和 2 进行整合。激酶抑制剂在两种不同情况下作为 AR 通路治疗的辅助药物——肿瘤中的 PI3K/AKT 激活令人兴奋的是，最近的一项研究发现，肿瘤中 PTEN 缺失和 FGFR 激活，并产生自分泌 FGF8/FGF9。基于我们早期工作启动的 AKT 和 AR 联合抑制的临床试验证明了管理核心将显着改善 PTEN 缺失前列腺癌患者的生存率。监督项目之间、NCI 科学人员以及其他 DRSC 之间的整合。总的来说，我们的研究将验证各种联合治疗方案，结合分子治疗用于患者选择的生物标志物，作为临床转化的关键一步此外，药物和靶点。这里的研究与多种癌症类型广泛相关。

项目成果

期刊论文数量（39）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dual inhibition of AKT-mTOR and AR signaling by targeting HDAC3 in PTEN- or SPOP-mutated prostate cancer.

通过靶向 PTEN 或 SPOP 突变前列腺癌中的 HDAC3 双重抑制 AKT-mTOR 和 AR 信号传导

DOI：
10.15252/emmm.201708478
发表时间：
2018-04
期刊：
EMBO molecular medicine
影响因子：
11.1
作者：
Yan Y;An J;Yang Y;Wu D;Bai Y;Cao W;Ma L;Chen J;Yu Z;He Y;Jin X;Pan Y;Ma T;Wang S;Hou X;Weroha SJ;Karnes RJ;Zhang J;Westendorf JJ;Wang L;Chen Y;Xu W;Zhu R;Wang D;Huang H
通讯作者：
Huang H

The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1.

前列腺癌的神经内分泌转变是动态的并且依赖于 ASCL1。

DOI：
10.1101/2024.04.09.588557
发表时间：
2024
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Romero,Rodrigo;Chu,Tinyi;González-Robles,TaniaJ;Smith,Perianne;Xie,Yubin;Kaur,Harmanpreet;Yoder,Sara;Zhao,Huiyong;Mao,Chenyi;Kang,Wenfei;Pulina,MariaV;Lawrence,KaylaE;Gopalan,Anuradha;Zaidi,Samir;Yoo,Kwangmin;Choi,Jungmin
通讯作者：
Choi,Jungmin

Patient derived organoids to model rare prostate cancer phenotypes.

DOI：
10.1038/s41467-018-04495-z
发表时间：
2018-06-19
期刊：
Nature communications
影响因子：
16.6
作者：
Puca L;Bareja R;Prandi D;Shaw R;Benelli M;Karthaus WR;Hess J;Sigouros M;Donoghue A;Kossai M;Gao D;Cyrta J;Sailer V;Vosoughi A;Pauli C;Churakova Y;Cheung C;Deonarine LD;McNary TJ;Rosati R;Tagawa ST;Nanus DM;Mosquera JM;Sawyers CL;Chen Y;Inghirami G;Rao RA;Grandori C;Elemento O;Sboner A;Demichelis F;Rubin MA;Beltran H
通讯作者：
Beltran H

PRC2-Inactivating Mutations in Cancer Enhance Cytotoxic Response to DNMT1-Targeted Therapy via Enhanced Viral Mimicry.