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：
8136596
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/8136596
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患有妇科恶性肿瘤的女性的治疗结果。作为一名医学博士/博士，我拥有在体外使用人类妇科癌细胞系进行分子和细胞生物学的实验室经验。我寻求 K23 指导的以患者为导向的研究职业发展奖，以扩展我在转化临床试验方面的技能，并获得临床研究 (MSCR) 理学硕士学位。这项多学科 K23 提案使用已建立的癌细胞系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子宫内膜癌治疗药物的作用。子宫内膜癌是美国女性第四大常见癌症，该疾病的死亡率在过去十年中增加了 227%。肥胖和糖尿病与常见子宫内膜癌（I 型或子宫内膜癌）的较高复发率和死亡率有关。我假设二甲双胍将充当 mTOR 抑制剂，并成为治疗受肥胖和胰岛素抵抗影响的疾病的有效化疗药物。为了了解二甲双胍的抗肿瘤潜力，我将评估二甲双胍对四种子宫内膜癌细胞系和人子宫内膜癌细胞原代培养物中二甲双胍细胞信号转导关键靶标的增殖、凋亡和表达的影响。与此同时，我将通过基因表达谱评估肥胖和非肥胖女性子宫内膜癌的生物学特性，以确定与二甲双胍配对的适当靶向疗法，并且我将在体外评估这些药物与二甲双胍之间的协同作用。最后，我将通过比较每位患者在二甲双胍治疗 2-4 周后的子宫内膜活检和子宫切除标本，确定二甲双胍对患有子宫内膜癌的肥胖和糖尿病女性的子宫内膜的影响。我们将在组织样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中的发现相关联。在此术前窗口期间的治疗使我们能够安全地评估二甲双胍对人子宫内膜癌的体内生物学效应。 K23 奖项提供的培训、课程、指导和 75% 受保护的研究时间将使我能够成为一名转化研究员和临床试验师。通过 K23 奖项，我将获得技能和大量工作，以成功竞争同行评审的资助支持，并最终获得我的第一个 R01。我的总体希望是看到我的实验室科学结果能够应用于临床试验和开发出对与妇科癌症作斗争的女性的生活产生重大影响的疗法。