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.

Public Health Relevance

Obesity and diabetes have been linked to poorer survival and increased recurrence rates in endometrial cancer. We hypothesize that metformin will behave as a novel mTOR inhibitor and prove to be an effective chemotherapeutic strategy for a disease undoubtedly impacted by insulin resistance. Thus, the overall goal of this proposal is to investigate the potential benefit of metformin as a targeted therapy for the treatment of endometrial cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
Application #
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lim, Susan E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Obstetrics & Gynecology
Schools of Medicine
Chapel Hill
United States
Zip Code
Jones, Hannah M; Fang, Ziwei; Sun, Wenchuan et al. (2017) Atorvastatin exhibits anti-tumorigenic and anti-metastatic effects in ovarian cancer in vitro. Am J Cancer Res 7:2478-2490
Jackson, Amanda L; Sun, Wenchuan; Kilgore, Joshua et al. (2017) Phenformin has anti-tumorigenic effects in human ovarian cancer cells and in an orthotopic mouse model of serous ovarian cancer. Oncotarget 8:100113-100127
Stine, Jessica E; Guo, Hui; Sheng, Xiugui et al. (2016) The HMG-CoA reductase inhibitor, simvastatin, exhibits anti-metastatic and anti-tumorigenic effects in ovarian cancer. Oncotarget 7:946-60
Kilgore, Joshua; Jackson, Amanda L; Clark, Leslie H et al. (2016) Buformin exhibits anti-proliferative and anti-invasive effects in endometrial cancer cells. Am J Transl Res 8:2705-15
Qiu, Haifeng; Li, Jing; Clark, Leslie H et al. (2016) JQ1 suppresses tumor growth via PTEN/PI3K/AKT pathway in endometrial cancer. Oncotarget 7:66809-66821
Suen, Alisa A; Jefferson, Wendy N; Wood, Charles E et al. (2016) SIX1 Oncoprotein as a Biomarker in a Model of Hormonal Carcinogenesis and in Human Endometrial Cancer. Mol Cancer Res 14:849-58
Zhang, Lu; Han, Jianjun; Jackson, Amanda L et al. (2016) NT1014, a novel biguanide, inhibits ovarian cancer growth in vitro and in vivo. J Hematol Oncol 9:91
Roque, Dario R; Makowski, Liza; Chen, Ting-Huei et al. (2016) Association between differential gene expression and body mass index among endometrial cancers from The Cancer Genome Atlas Project. Gynecol Oncol 142:317-22
Suri, Anuj; Sheng, Xiugui; Schuler, Kevin M et al. (2016) The effect of celecoxib on tumor growth in ovarian cancer cells and a genetically engineered mouse model of serous ovarian cancer. Oncotarget 7:39582-39594
Han, Xiaoyun; Sheng, Xiugui; Jones, Hannah M et al. (2015) Evaluation of the anti-tumor effects of lactate dehydrogenase inhibitor galloflavin in endometrial cancer cells. J Hematol Oncol 8:2

Showing the most recent 10 out of 21 publications