Metformin as a Novel Chemotheraeutic Strategy for the Treatment of Endometrial Ca

描述(由申请者提供)：我的长期目标是成为一名独立资助的学术临床医生兼科学家，进行转译研究，以改善妇科恶性肿瘤患者的预后。作为一名医学博士，我在分子和细胞生物学方面有使用体外培养的人类妇科癌细胞系的实验室经验。我寻求K23导师以患者为导向的研究职业发展奖，以扩大我在转化型临床试验中的技能，并获得临床研究(MSCR)理学硕士学位。这项多学科的K23提案使用已建立的癌细胞株和来自子宫内膜肿瘤的原代培养物、基因表达谱和临床试验来评估二甲双胍作为治疗子宫内膜癌的药物。子宫内膜癌是美国女性中第四常见的癌症，在过去十年中，该疾病的死亡率增加了227%。肥胖和糖尿病与常见的子宫内膜癌(I型或子宫内膜样癌)的复发率和死亡率有关。我假设二甲双胍将作为一种mTOR抑制剂，并成为一种有效的化疗药物，治疗受肥胖和胰岛素抵抗影响的疾病。为了了解二甲双胍的抗肿瘤潜能，我将评估二甲双胍对四种子宫内膜癌细胞系和原代培养的人子宫内膜癌细胞增殖、凋亡和二甲双胍细胞信号转导关键靶点表达的影响。同时，我将通过基因表达谱来评估肥胖和非肥胖女性子宫内膜癌的生物学，以确定合适的靶向治疗与二甲双胍配合，并将在体外评估这些药物与二甲双胍之间的协同作用。最后，我将通过比较每个患者在使用二甲双胍治疗2-4周后的子宫内膜活检和子宫切除标本，来确定二甲双胍对患有子宫内膜癌的肥胖和糖尿病妇女的子宫内膜的影响。我们将在组织标本中探索二甲双胍对增殖、凋亡和下游信号通路的影响，并将其与我们在体外培养的子宫内膜癌细胞的研究结果相关联。在这一术前窗口期的治疗使我们能够安全地评估二甲双胍在体内对人子宫内膜癌的生物学效应。K23奖项提供的培训、课程、指导和75%的受保护研究时间将使我能够确立自己作为翻译研究员和临床试验人员的地位。通过K23奖项，我将获得技能和一系列工作，以成功竞争同行评审的拨款支持，并最终获得我的第一个R01。我的总体希望是看到我的长凳科学的结果导致临床试验和疗法的开发，这些疗法对与妇科癌症作斗争的女性的生活产生重大影响。

DESCRIPTION (provided by applicant): My long-term goal is to become an independently-funded academic clinician-scientist, performing translational research to improve outcomes for women with gynecologic malignancies. As an MD/PhD, I have laboratory experience in molecular and cellular biology using human gynecologic cancer cell lines in vitro. I seek a K23 Mentored Patient-Oriented Research Career Development Award to expand my skills in translational clinical trials and obtain a Masters of Science degree in Clinical Research (MSCR). This multi- disciplinary K23 proposal uses established cancer cell lines and primary cultures from endometrial tumors, gene expression profiling, and a clinical trial, to assess metformin as a drug for endometrial cancer therapy. Endometrial cancer is the fourth most common cancer among women in the United States, and the death rate from this disease has increased by 227% over the past ten years. Obesity and diabetes are linked to higher recurrence rates and death in the common form of endometrial cancer (type I, or endometriod). I hypothesize that metformin will act as an mTOR inhibitor and be an effective chemotherapeutic agent for a disease so impacted by obesity and insulin resistance. To understand metformin's anti-tumorigenic potential, I will assess the effects of metformin on proliferation, apoptosis and expression of key targets of metformin cell signaling in four endometrial cancer cell lines and in primary cultures of human endometrial cancer cells. In parallel, I will evaluate the biology of endometrial cancer in obese and non-obese women through gene expression profiling to identify appropriate targeted therapies to pair with metformin, and I will assess synergy between these agents and metformin in vitro. Lastly, I will determine the effect of metformin on the endometrium of obese and diabetic women with endometrial cancer by comparing each patient's endometrial biopsy with their hysterectomy specimen following 2-4 weeks of treatment with metformin. The effect of metformin on proliferation, apoptosis and downstream signaling pathways will be explored in tissue specimens and correlated to our findings with cultured endometrial cancer cells in vitro. Therapy during this preoperative window allows us to evaluate safely the biologic effect of metformin on human endometrial cancer in vivo. The training, curriculum, mentoring and 75% protected research time provided by the K23 award will enable me to establish myself as a translational researcher and clinical trialist. Through the K23 award, I will acquire the skills and a body of work to compete successfully for peer-reviewed grant support and ultimately, my first R01. My overall hope is to see the results of my bench science lead to clinical trials and the development of therapies that have a significant impact on the lives of women battling gynecologic cancers.