Identifying and Characterizing Therapeutic Targets in Adrenal Cancer

肾上腺癌治疗靶点的识别和表征

基本信息

批准号：
10012767
负责人：
Katja KISELJAKVASSILIADES
金额：
$ 21万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10012767
关键词：
Acute Adrenal Gland Cancer Adrenal Gland Neoplasms Adrenal Glands Adrenocortical carcinoma Area Bioinformatics Biological Assay Cell Cycle Cell Line Cells Chronic Cisplatin Clinical Clinical Research Clinical Trials Collaborations Colorado Communities DNA Damage Data Data Analyses Databases Development Diagnosis Distant Metastasis Dose Doxorubicin Embryo Endocrine Ensure Etoposide Future Gene Targeting Genetic Genomics Goals Growth Human Impairment In Vitro Insecticides International Laboratories Laboratory Research Learning Leucine Zippers Literature Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Mentors Mentorship Michigan Mitotic Modality Modeling Molecular Neoplasms Oncogenes Oncogenic Oncology Group Operative Surgical Procedures Outcome Study Pathway interactions Patients Pharmaceutical Preparations Phase Phosphotransferases Physicians Pre-Clinical Model Program Development Progression-Free Survivals Protein Array Proteomics Published Database Recurrence Regimen Research Research Personnel Research Technics Resectable Resistance Role Sampling Scientist Signal Transduction Soft Agar Assay Techniques Testing Time Tissues Toxic effect Training Translating Translational Research Tumor Biology Universities Unresectable Up-Regulation Work Xenograft Model Xenograft procedure attenuation base carcinogenesis career career development chemotherapeutic agent chemotherapy clinical practice design differential expression experience experimental study in vitro Model in vivo in vivo Model kinase inhibitor mouse model multidisciplinary neoplastic cell new therapeutic target novel outcome forecast overexpression phase 1 study programs protein kinase inhibitor response rho senescence skills small hairpin RNA targeted treatment therapeutic target transcriptome sequencing tumor tumor growth tumorigenesis tumorigenic

项目摘要

Project Summary Adrenocortical carcinoma (ACC) is an aggressive, fatal cancer with five-year survival less than 35%. Surgery remains the only chance of a cure; however, many tumors are unresectable at time of presentation. Lack of human ACC research models has significantly limited progress in the field. Recent establishment of Multi- Disciplinary Adrenal Tumor group at University of Colorado (CU) provides an ideal platform for a collaborative research to advance the field. We have recently established the first new human ACC cell lines and ACC patient derived xenografts (PDX). In parallel, using bioinformatic analyses of published databases, I have identified novel kinases dysregulated in ACC. My initial focus is on maternal embryonic leucine zipper kinase (MELK) which is upregulated 5-25-fold in 40-50% of ACC and low or absent in normal adrenal tissue. Increased MELK expression is correlated with a shorter survival in patients with ACC. Preliminary data support my hypothesis that MELK confers an oncogenic signal by increasing tumorigenesis, proliferation and survival in vitro. The goals for this proposal is to use our ACC models to dissect the mechanism and functional significance of dysregulated kinases such as MELK in ACC. Studies will dissect the functional role of MELK and its downstream targets in our newly developed ACC cell lines; identify potential escape mechanisms from MELK inhibition; and examine whether inhibiting MELK with or without blocking escape pathways leads to decrease tumor growth in our new PDX models. My ultimate career goal is to become an independent physician scientist in the area of endocrine neoplasia with a focus in ACC. Towards this goal, my mentored career development program will allow me: 1) to acquire new technical laboratory skills in in vitro and in vivo assays; 2) to expand my training in bioinformatics using genomic and proteomic platforms 3) to expand training into future phase I studies 4) to promote integration of research findings to clinical practice. This proposal includes a strong and diverse mentoring team including Dr. Wierman with extensive mentoring experience and expertise in tumor biology focused on endocrine neoplasia, Dr. Schweppe, a signal transduction expert with extensive experience in genomic and proteomic approaches in tumor biology and Dr. Leong who integrates research from PDX in GI cancer to Phase I studies. They will ensure expertise in experiment design, new laboratory, and clinical research skills, critical data analysis and advice about career development. Collaborators will provide hands on additional training in bioinformatics, as well as development of cutting edge research techniques and models. In addition Dr. Hammer, University of Michigan, an internationally renowned expert in ACC, will provide mentorship to ensure that I am integrated into the ACC community by developing collaborations which will amplify my work. The outcome of these studies will have a significant impact for the field by allowing testing of novel therapeutic targets in newly developed research models with an ultimate aim to translate these studies into human trials of new treatment modalities for patients with ACC.

项目概要肾上腺皮质癌 (ACC) 是一种侵袭性致命癌症，五年生存率低于 35%。外科手术仍然是治愈的唯一机会；然而，许多肿瘤在就诊时无法切除。缺乏人类 ACC 研究模型极大地限制了该领域的进展。最近成立的多科罗拉多大学 (CU) 的纪律性肾上腺肿瘤小组为协作提供了理想的平台研究以推进该领域的发展。我们最近建立了第一个新的人类 ACC 细胞系和 ACC 患者来源的异种移植物（PDX）。与此同时，通过对已发表数据库的生物信息学分析，我得到了鉴定出 ACC 中失调的新激酶。我最初的重点是母体胚胎亮氨酸拉链激酶 (MELK) 在 40-50% 的 ACC 中上调 5-25 倍，而在正常肾上腺组织中表达较低或不存在。 MELK 表达增加与 ACC 患者的生存期较短相关。初步数据支持我的假设，即 MELK 通过增加肿瘤发生、增殖和体外存活。该提案的目标是使用我们的 ACC 模型来剖析机制和功能 ACC 中失调的激酶（例如 MELK）的重要性。研究将剖析 MELK 的功能作用及其在我们新开发的 ACC 细胞系中的下游靶标；识别潜在的逃逸机制 MELK 抑制；并检查抑制 MELK 并阻断逃逸途径或不阻断逃逸途径是否会导致在我们的新 PDX 模型中减少肿瘤生长。我的最终职业目标是成为一个独立的人内分泌肿瘤领域的医师科学家，重点研究 ACC。为了这个目标，我的导师职业发展计划将使我能够：1）获得体外和体内的新技术实验室技能化验； 2) 使用基因组和蛋白质组平台扩展我的生物信息学培训 3) 扩展培训 4）促进研究成果与临床实践的结合。这个提议包括一支强大而多元化的指导团队，其中包括具有丰富指导经验的 Wierman 博士， Schweppe 博士是一位信号转导专家，专注于内分泌肿瘤领域的肿瘤生物学专业知识 Leong 博士在肿瘤生物学基因组学和蛋白质组学方法方面拥有丰富的经验，他整合了从胃肠道癌症中的 PDX 研究到 I 期研究。他们将确保实验设计、新实验室和临床研究技能、关键数据分析以及有关职业发展的建议。合作者将提供生物信息学方面的额外培训以及尖端技术的开发研究技术和模型。此外，国际知名密歇根大学 Hammer 博士 ACC 专家将提供指导，确保我通过发展融入 ACC 社区合作将扩大我的工作。这些研究的结果将对通过允许在新开发的研究模型中测试新的治疗靶点以达到最终目标将这些研究转化为 ACC 患者新治疗方式的人体试验。