Revision: MD Anderson Gynecologic SPORE for Uterine Cancers

修订版：MD 安德森妇科孢子治疗子宫癌

基本信息

批准号：
9377854
负责人：
RUSSELL R BROADDUS
金额：
$ 19.2万
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 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9377854
关键词：
Address Adenosine Atypical hyperplasia Award Biological Markers Biopsy CTNNB1 gene Cancer Center Cancer Patient Carcinoma Characteristics Clinical Clinical Trials Combined Modality Therapy Complex DNA Sequence Alteration Development Diagnosis Disease Drug Delivery Systems Endometrial Carcinoma Endometrioid Carcinoma Epidemic Evaluation Genomics Goals Gynecologic Gynecology Hormonal Immune Immunosuppression Immunosuppressive Agents Immunotherapy Intrauterine Devices Lesion Link Liposomes Malignant Neoplasms Molecular Molecular Profiling Mutation Neoplasm Circulating Cells Obesity PI3K/AKT PTEN gene Parents Pathologic Pathway interactions Patients Pharmacology Phase Phase I Clinical Trials Polymers Premalignant Prevention Prevention Research Prevention strategy Progestins Proteins Recruitment Activity Recurrence Research Research Personnel Research Project Grants Resistance Resources Risk Role SDZ RAD Scientific Advances and Accomplishments Scientist Serous Signal Transduction Small Interfering RNA Specialized Program of Research Excellence Subgroup Testing Therapeutic Toxic effect Translational Research United States Uterine Cancer Woman anticancer research base beta catenin biomarker panel cancer heterogeneity cancer recurrence cancer type career clinical decision-making combinatorial design experience high risk improved improved outcome innovation mTOR Inhibitor molecular diagnostics molecular marker neoplastic cell next generation sequencing novel novel strategies novel therapeutics overexpression phase II trial programs resistance mechanism response biomarker success targeted agent targeted treatment therapeutic target tissue biomarkers translational impact translational scientist tumor tumor microenvironment tumor progression

项目摘要

Overall Abstract The goals of the Endometrial Cancer SPORE at MD Anderson Cancer Center are the following: 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. This parent 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. It is hypothesized that CTNNB1 mutation and Wnt pathway activation promote immunosuppression in the tumor microenvironment, which enables tumor progression and recurrence. Project 3, “EphA2 Targeting in Uterine Carcinoma,” focuses on the therapeutic target, EphA2, which is overexpressed in higher grade endometrioid carcinomas and 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; developed by Project 3 investigators) that targets EphA2 by delivering short interfering RNA into tumor cells via a neutral liposome nanovehicle. Project 4, “Rational Combinatorial Therapy in Endometrial Cancer,” will evaluate tumor molecular changes from biopsies 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 testing platform to evaluate mechanisms responsible for adaptive resistance to targeted therapies in order to enable design of improved combination therapies for endometrial cancer. The proposed expansion project will elaborate upon the themes of Project 2 and examine the impact of PTEN loss and loss of CD73-generated adenosine signaling in the development of an immunosuppressive tumor microenvironment. Completion of this expansion project and Project 2 will help us to identify more precisely molecular modifiers of the local tumor microenvironment and will aid in the development of more rational immune-based therapy strategies.

总体抽象 MD Anderson Cancer Central的子宫内膜癌孢子的目标如下：1）发展新颖晚期/复发性子宫内膜癌癌症癌症癌症和侵略性亚型的治疗策略； 2）促进小说对预防和保守治疗高风险癌症病变和保守疗法的策略策略低年级子宫内膜癌； 3）将分子诊断纳入临床决策；并通过职业增强和发展研究计划。跨越子宫内膜癌异质性广度的科学问题，以影响许多病人1。复杂的非典型增生和1级子宫内膜类子宫内膜癌，包括一项II期试验 MTOR抑制剂Everolimus，以改善标准保守疗法（孕妇的孕妇内装置）并且与创新的分子熟练和药理方法配对，以进一步提高施工治疗选择2，“ CTNNB1突变和Wnt途径激活子宫内膜化子宫内膜癌，“侧重于靶向方法和分子机制子宫内膜癌的临床攻击性亚型。和Wnt途径激活收益器微环境，可实现肿瘤进度和复发。 Target, Epha2, Which Is OverExpressed in Higher Grade Endometrioid CARCINOMAS CARCINOMA CARCINOMA and is is is is is is is is is is is is is is is is is is is is is is. 与整体生存差有关。治疗（Epharna;由项目3调查人员开发的）通过提供短暂的干扰来靶向EPHA2 RNA通过中性脂质体纳米螺旋体进入肿瘤细胞。子宫内膜癌”将评估在联合试验试验期间采购的活检的肿瘤分子变化 PARP和PI3K途径的靶向治疗，以鉴定子宫内膜患者的益处生物标志物癌症。对靶向疗法的抗性，以便设计改进的子宫内膜组合癌症。 PTEN损失和CD73产生的腺苷信号传导的损失和免疫性开发中肿瘤的微环境。精确的局部肿瘤微环境的分子修饰剂，将有助于发展更多理性免疫治疗策略。