MD Anderson Gynecologic SPORE for Uterine Cancers

总体摘要/摘要 MD安德森癌症中心子宫内膜(子宫)癌孢子的总体目标是进行 用于预防和治疗子宫内膜癌的高度创新的转化研究。包含 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/复发子宫内膜癌和侵袭性亚型；2)促进未治疗的新策略 高危及低度癌前病变预防和保守治疗的临床需求 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 发展研究计划。在过去的5年里，我们的孢子以极高的 高效的转化型研究团队，帮助定义了临床和分子异质性 子宫内膜癌。该提案包括4个针对科学问题的翻译研究项目。 这跨越了子宫内膜癌异质性的广度，以努力影响尽可能多的患者。 项目1，“预防和保守管理复杂非典型肺炎的有针对性的新战略” 子宫内膜增生症与1级子宫内膜样癌：包括使用mTOR抑制剂的II期试验 埃博利莫斯用于改进标准保守治疗(孕激素洗脱宫内节育器)，并与 进一步推进保守治疗的创新分子图谱和药理学方法 选择。项目2，CTNNB1突变和Wnt通路激活定义临床侵袭性子宫内膜样变 子宫内膜癌，集中在靶向治疗和分子机制基础上的临床 侵袭性子宫内膜样癌亚型，由β-连环蛋白突变和 下游Wnt通路被激活。项目3“EphA2在子宫癌中的靶向”，重点是 治疗靶点EphA2。EphA2在高级别子宫内膜样癌和子宫内膜样癌中的过度表达 浆液性癌与总体存活率低有关。一期临床试验将评估其疗效。 靶向EphA2的新型治疗性药物(EPHARNA)的毒性 通过中性脂质体纳米载体治疗肿瘤细胞。这种疗法是由Project 3的研究人员开发的。 项目4，“确定子宫内膜癌新靶向治疗组合的框架”， 将评估在PARP和PI3K联合试验期间获得的样本中的肿瘤分子变化 路径靶向治疗以确定对子宫内膜癌患者有益的生物标记物。这是成对的 通过实施一个平台来评估对靶向治疗产生适应性耐药的机制 以便能够合理地设计改进的联合疗法。四个核心将支持这些项目- 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。

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.