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

二甲双胍作为治疗子宫内膜钙的新型化疗策略

基本信息

批准号：
8320344
负责人：
Victoria Lin Bae-Jump
金额：
$ 17.09万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8320344
关键词：
5&apos -AMP-activated protein kinase Aftercare Aging Apoptosis Biguanides Biology Biopsy Body Weight decreased Cancer Patient Cancer cell line Caring Cell Culture Techniques Cell Cycle Arrest Cell Line Cell Proliferation Cessation of life Chemosensitization Clinical Clinical Research Clinical Trials Combined Modality Therapy Data Death Rate Development Diabetes Mellitus Diagnosis Diagnostic Diet Disease Doctor of Philosophy Drug Combinations Drug effect disorder Educational Curriculum Endometrial Endometrial Carcinoma Endometrial Neoplasms Endometrium Epidemiology Estrogen Receptors Exercise Feedback Female Frequencies Funding Future Gene Expression Gene Expression Profiling Genes Goals Growth Factor Growth Factor Receptors Gynecologic Hormonal Human Hysterectomy In Vitro Induction of Apoptosis Inhibition of Cell Proliferation Insulin Insulin Resistance Intervention Knowledge Laboratories Lead Life Style Link Malignant - descriptor Malignant Female Reproductive System Neoplasm Malignant Neoplasms Master of Science Measures Mediating Mentored Patient-Oriented Research Career Development Award Mentors Metformin Methods Microarray Analysis Molecular Abnormality Molecular Profiling Molecular and Cellular Biology Non obese Non-Insulin-Dependent Diabetes Mellitus Obesity Operative Surgical Procedures Oral Outcome PTEN gene Paclitaxel Pathway interactions Patients Peer Review Grants Pharmaceutical Preparations Phase Phosphorylation Phosphorylation Inhibition Population Progesterone Receptors Recurrence Regulation Research Research Personnel Research Training Risk Risk Factors Route Science Scientist Secondary to Signal Pathway Signal Transduction Specimen Staging Therapeutic Therapeutic Agents Time Tissues Toxic effect Training Translational Research Tumor-Derived United States United States National Institutes of Health Weight Woman Work base cancer cell cancer risk cancer therapy cancer type carcinogenesis chemotherapeutic agent cost diabetic diabetic patient experience human FRAP1 protein improved in vivo indexing inhibitor/antagonist innovation mTOR Inhibitor mTOR inhibition mortality multiple drug use neoplastic non-diabetic novel patient population pre-clinical response skills therapeutic target therapy development translational clinical trial treatment strategy tumor tumorigenic

项目摘要

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.

描述（由申请人提供）：我的长期目标是成为一名独立资助的学术临床医生 - 科学家，进行转化研究，以改善妇科恶性肿瘤女性的结果。作为MD/PHD，我在体外使用人类妇科癌细胞系具有实验室经验。我寻求K23指导的以患者为导向的研究职业发展奖，以扩大我在转化临床试验方面的技能，并获得临床研究硕士学位（MSCR）。该多学科的K23提案使用了从子宫内膜肿瘤，基因表达分析和临床试验中建立的癌细胞系和原发性培养物来评估二甲双胍作为子宫内膜癌症治疗的药物。子宫内膜癌是美国女性中第四个最常见的癌症，在过去的十年中，这种疾病的死亡率增加了227％。肥胖症和糖尿病与子宫内膜癌（I型或子宫内膜异位）的共同形式的复发率和死亡有关。我假设二甲双胍将充当MTOR抑制剂，并成为受肥胖和胰岛素抵抗影响的疾病的有效化学治疗剂。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中二甲双胍细胞信号传导的增殖，凋亡和表达的影响，以及人子宫内膜癌细胞的原发性培养物。同时，我将通过基因表达分析评估肥胖和非肥胖妇女子宫内膜癌的生物学，以鉴定适当的靶向疗法与二甲双胍配对，我将评估这些药物与体外二甲双胍之间的协同作用。最后，我将通过将每个患者的子宫内膜活检与二甲双胍治疗2-4周后，通过将每个患者的子宫内膜活检与子宫内膜切除术样本进行比较，确定二甲双胍对肥胖和子宫内膜癌子宫内膜子宫内膜的影响。将在组织样品中探索二甲双胍对增殖，凋亡和下游信号传导途径的影响，并与我们与培养的子宫内膜癌细胞的发现相关。在此术前窗口中的治疗使我们能够安全地评估二甲双胍对体内人子宫内膜癌的生物学作用。 K23奖提供的培训，课程，指导和75％的保护时间将使我能够确立自己的翻译研究人员和临床试验者。通过K23奖，我将获得成功竞争的技能和一项工作，以获得同行评审的赠款支持，最终是我的第一个R01。我的总体希望是看到我的基准科学的结果导致临床试验以及对与妇科癌作斗争的妇女生活产生重大影响的疗法的发展。