MD Anderson Gynecologic SPORE for Uterine Cancers

MD 安德森妇科 SPORE 治疗子宫癌

基本信息

批准号：
10249382
负责人：
RUSSELL R BROADDUS
金额：
$ 21.5万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10249382
关键词：
Address Atypical hyperplasia Award Bioinformatics Biological Markers Biometry CTNNB1 gene Cancer Center Carcinoma Characteristics Clinical Clinical Trials Combined Modality Therapy Complex Country DNA Sequence Alteration Development Diagnosis Disease Drug Delivery Systems Endometrial Endometrial Carcinoma Endometrioid Carcinoma Evaluation Genomics Goals Gynecologic Heterogeneity Hormonal Intrauterine Devices Lesion Link Liposomes Molecular Molecular Profiling Mutation Neoplasm Circulating Cells Obesity Obesity Epidemic Pathologic Pathology Pathway interactions Patients Pharmacology Phase Phase I Clinical Trials Polymers Prevention Prevention Research Prevention strategy Progestins Proteins Recurrence Research Research Personnel Research Project Grants Resistance Resources Risk SDZ RAD Sampling Scientific Advances and Accomplishments Scientist Serous Small Interfering RNA Specialized Program of Research Excellence Subgroup Therapeutic Toxic effect Translational Research United States Uterine Cancer Uterus Woman anticancer research base beta catenin biomarker panel cancer heterogeneity cancer type career clinical decision-making combinatorial design experience high risk improved improved outcome innovation interest mTOR Inhibitor molecular diagnostics molecular marker neoplastic cell new therapeutic target next generation sequencing novel novel strategies novel therapeutics overexpression phase II trial premalignant programs recruit resistance mechanism response biomarker success targeted agent targeted treatment therapeutic target tissue biomarkers translational impact translational scientist tumor

项目摘要

Overall SUMMARY/ABSTRACT The overall goal of the Endometrial (Uterine) Cancer SPORE at MD Anderson Cancer Center is to conduct highly innovative translational research for the prevention and treatment of endometrial cancer. Encompassed within this broad overall goal are the following more specific goals: 1) develop novel therapeutic strategies for advanced/recurrent endometrial cancer and aggressive subtypes; 2) promote novel strategies for unmet clinical needs in prevention and conservative therapy of high-risk precancerous lesions and low grade endometrial cancer; 3) incorporate molecular diagnostics into clinical decision-making; and 4) recruit and support new investigators in endometrial cancer research through the Career Enhancement and Developmental Research Programs. Over the last 5 years, our SPORE has led the field with a highly productive translational research team that has helped to define the clinical and molecular heterogeneity of endometrial cancer. This proposal includes 4 translational research projects addressing scientific problems that span the breadth of endometrial cancer heterogeneity in an effort to impact as many patients as possible. Project 1, “Novel Targeted Strategies for Prevention and Conservative Management of Complex Atypical Hyperplasia and Grade 1 Endometrioid Endometrial Cancer,” includes a phase II trial using the mTOR inhibitor everolimus to improve standard conservative therapy (progestin-eluting intrauterine device) and is paired with innovative molecular profiling and pharmacologic approaches to further advance conservative treatment options. Project 2, “CTNNB1 Mutation and Wnt Pathway Activation Define Clinically Aggressive Endometrioid Endometrial Carcinoma,” focuses on targeted therapeutics and molecular mechanisms underlying a clinically aggressive subtype of endometrioid endometrial cancer that is driven through beta-catenin mutation and downstream Wnt pathway activation. Project 3, “EphA2 Targeting in Uterine Carcinoma,” focuses on the therapeutic target, EphA2. EphA2 is overexpressed especially in higher grade endometrioid carcinomas and in serous carcinoma and is associated with poor overall survival. A phase I clinical trial will evaluate the efficacy and toxicity of a novel therapeutic (EPHARNA) that targets EphA2 by delivering short interfering RNA into tumor cells via a neutral liposome nanovehicle. This therapeutic was developed by Project 3 investigators. Project 4, “A Framework for Identification of Novel Targeted Therapy Combinations in Endometrial Cancer,” will evaluate tumor molecular changes from samples procured during a combinatorial trial of PARP and PI3K pathway targeted therapy to identify biomarkers of benefit for patients with endometrial cancer. This is paired with implementing a platform to evaluate mechanisms responsible for adaptive resistance to targeted therapies in order to enable a rational design of improved combination therapies. Four Cores will support these projects- Administrative Core, Pathology Core, Biomarkers Core, and Biostatistics and Bioinformatics Core.

总体总结/摘要 MD 安德森癌症中心子宫内膜（子宫）癌 SPORE 的总体目标是进行预防和治疗子宫内膜癌的高度创新转化研究。在这个广泛的总体目标中，有以下更具体的目标：1）开发新的治疗策略晚期/复发性子宫内膜癌和侵袭性亚型；2) 促进未满足治疗的新策略高危癌前病变和低级别癌前病变预防和保守治疗的临床需要子宫内膜癌；3) 将分子诊断纳入临床决策；4) 招募和通过职业提升和支持子宫内膜癌研究的新研究者过去 5 年里，我们的 SPORE 在该领域处于领先地位。富有成效的转化研究团队，帮助定义了临床和分子异质性该提案包括 4 个解决科学问题的转化研究项目。跨越子宫内膜癌异质性的广度，努力影响尽可能多的患者。项目 1，“复杂非典型疾病预防和保守治疗的新型针对性策略” 增生和 1 级子宫内膜样子宫内膜癌”，包括使用 mTOR 抑制剂的 II 期试验依维莫司可改善标准保守治疗（孕激素洗脱宫内节育器），并与创新的分子分析和药理学方法进一步推进保守治疗选项项目 2，“CTNNB1 突变和 Wnt 通路激活定义临床侵袭性子宫内膜样蛋白”。子宫内膜癌”，重点关注临床上潜在的靶向治疗和分子机制子宫内膜样子宫内膜癌的侵袭性亚型，由 β-连环蛋白突变驱动，下游 Wnt 通路激活项目 3“子宫癌中的 EphA2 靶向”重点关注治疗靶点 EphA2 尤其是在高级子宫内膜样癌中过度表达。浆液性癌且与较差的总体生存率相关，I 期临床试验将评估其疗效。通过将短干扰 RNA 递送至 EphA2 的新型疗法 (EPHARNA) 的毒性和毒性该疗法由 Project 3 研究人员开发。项目 4，“子宫内膜癌新型靶向治疗组合的识别框架” 将评估 PARP 和 PI3K 组合试验期间采集的样本的肿瘤分子变化途径靶向治疗，以确定对子宫内膜癌患者有益的生物标志物。实施一个平台来评估对靶向治疗产生适应性耐药的机制为了能够合理设计改进的联合疗法，四核将支持这些项目- 行政核心、病理学核心、生物标志物核心、生物统计学和生物信息学核心。