Revision: MD Anderson Gynecologic SPORE for Uterine Cancers

总体摘要 MD安德森癌症中心的子宫内膜癌孢子的目标如下：1）开发新的 晚期/复发性子宫内膜癌和侵袭性亚型的治疗策略; 2）促进新的 针对高危癌前病变预防和保守治疗中未满足的临床需求的策略， 低度子宫内膜癌; 3）将分子诊断纳入临床决策; 4）招募 并通过职业提升计划支持子宫内膜癌研究的新研究者， 发展研究计划。该母提案包括4个转化研究项目， 科学问题，跨越子宫内膜癌异质性的广度，努力影响尽可能多的 患者尽可能项目1，“预防和保守管理糖尿病的新的有针对性的策略” 复杂非典型增生和1级子宫内膜样子宫内膜癌”，包括一项II期试验， mTOR抑制剂依维莫司改善标准保守治疗（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相结合，以进一步推进保守的 治疗方案。项目2，“CTNNB 1突变和Wnt通路激活定义临床侵袭性 子宫内膜样子宫内膜癌”，重点是靶向治疗和分子机制， 子宫内膜癌的临床侵袭性亚型。假设CTNNB 1突变 和Wnt通路激活促进肿瘤微环境中的免疫抑制，这使得肿瘤微环境中的免疫抑制变得可能。 进展和复发。项目3，“EphA 2靶向子宫癌”，重点是治疗 靶向EphA 2，EphA 2在较高级别的类肉瘤和浆液性癌中过表达， 与总体生存率低有关。一项I期临床试验将评估一种新的 治疗剂（EPHARNA;由项目3研究者开发），其通过递送短干扰信号靶向EphA 2， 通过中性脂质体纳米载体将RNA导入肿瘤细胞。项目4，“合理组合疗法， 子宫内膜癌”，将评估在一项联合试验中获得的活组织检查的肿瘤分子变化 PARP和PI 3 K通路靶向治疗，以确定子宫内膜异位症患者获益的生物标志物 癌这与实现测试平台相结合，以评估负责自适应的机制。 对靶向治疗的耐药性，以便能够设计用于子宫内膜异位症的改进的组合疗法。 癌拟议的扩建项目将阐述项目2的主题，并审查 在免疫抑制剂的发展中，PTEN的丢失和CD 73产生的腺苷信号的丢失 肿瘤微环境这个扩建项目和项目2的完成将帮助我们确定更多 精确的分子修饰剂的局部肿瘤微环境，并将有助于发展更多的 合理的免疫治疗策略。

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.