While outcomes have substantially improved for many types of cancer, endometrial cancer incidence and deaths are on the rise, with the five year survival rate worse today than three decades ago. Inadequate sensitivity to chemotherapy is a primary cause of therapeutic failure. Our central hypothesis is that molecular inhibitors of key master regulators of cell cycle checkpoints, chosen based upon the knowledge of the tumor phenotype, synergize with chemotherapy and promote catastrophic tumor cell death. Our hypothesis is based on substantial preliminary data that sensitivity to chemotherapy depends upon the ability to enhance the number of cells in vulnerable periods of the cell cycle: taxanes are effective for cells in M, and platinum-based compounds and anthracyclines work primarily in S. Mutations in TP53, KRAS, PTEN, genes encoding PI3Kinase, and growth factor receptors such as FGFR2 predominate in endometrial cancer, altering master regulators of cell cycle checkpoints in unique and predictable ways. The rationale for this study is that, in order to address the alarming trend towards declining survival in endometrial cancer, we must overcome the impact of these driving mutations by combining standard chemotherapy with appropriate molecular inhibitors which can enhance cell sensitivity, a concept we term molecularly enhanced chemotherapy. We propose three specific aims to test and implement this strategy: 1. Determine the effect of mutations on checkpoint kinase activation associated with chemoresistance in specimens from the completed clinical trial, GOG 177, using pretreatment preserved tissue. Validate signaling targets of cell cycle control which relate to response to chemotherapy from fresh frozen tissue in GOG 210. 2. Overcome mechanisms of resistance to chemotherapy by manipulating cell cycle checkpoints with molecular inhibitors in cell models replicating endometrial tumor subtypes. 3. Optimize combinations of targeted agents with chemotherapy using human-in-mouse models. Thus, the major emphasis of this proposal is on the rational development of novel therapeutic strategies for endometrial cancer that have a significant potential for early translation to the clinic. The findings from this comprehensive research plan will be rapidly deployed in future clinical trials.

Public Health Relevance

While outcomes have substantially improved for many types of cancer, endometrial cancer incidence and deaths are on the rise, due in large part to inadequate sensitivity to chemotherapy. Our study is anticipated to redefine therapy for endometrial cancer by determining which endometrial tumor phenotypes are most associated with standard treatment failures and successfully integrating molecular therapies into chemotherapeutic regimens based on the specific tumor phenotypes. If successful, findings from this study of molecularly enhanced chemotherapy have the potential to significantly impact the design of future clinical trials for endometrial cancer as well as solid tumors at other sites.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Forry, Suzanne L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Iowa
Obstetrics & Gynecology
Schools of Medicine
Iowa City
United States
Zip Code
Gonzalez Bosquet, Jesus; Newtson, Andreea M; Chung, Rebecca K et al. (2016) Prediction of chemo-response in serous ovarian cancer. Mol Cancer 15:66
Reyes, Henry D; Carlson, Matthew J; Devor, Eric J et al. (2016) Downregulation of FOXO1 mRNA levels predicts treatment failure in patients with endometrial pathology conservatively managed with progestin-containing intrauterine devices. Gynecol Oncol 140:152-60
Devor, Eric J; Schickling, Brandon M; Reyes, Henry D et al. (2016) Cullin-5, a ubiquitin ligase scaffold protein, is significantly underexpressed in endometrial adenocarcinomas and is a target of miR-182. Oncol Rep 35:2461-5
Kavlashvili, Tamar; Jia, Yichen; Dai, Donghai et al. (2016) Inverse Relationship between Progesterone Receptor and Myc in Endometrial Cancer. PLoS One 11:e0148912
Meng, Xiangbing; Yang, Shujie; Zhang, Yuping et al. (2015) Genetic Deficiency of Mtdh Gene in Mice Causes Male Infertility via Impaired Spermatogenesis and Alterations in the Expression of Small Non-coding RNAs. J Biol Chem 290:11853-64
Schickling, Brandon M; England, Sarah K; Aykin-Burns, Nukhet et al. (2015) BKCa channel inhibitor modulates the tumorigenic ability of hormone-independent breast cancer cells via the Wnt pathway. Oncol Rep 33:533-8
Zhang, Yuping; Goodfellow, Renee; Li, Yujun et al. (2015) NEDD4 ubiquitin ligase is a putative oncogene in endometrial cancer that activates IGF-1R/PI3K/Akt signaling. Gynecol Oncol 139:127-33
Brachova, Pavla; Mueting, Samuel R; Carlson, Matthew J et al. (2015) TP53 oncomorphic mutations predict resistance to platinum‑ and taxane‑based standard chemotherapy in patients diagnosed with advanced serous ovarian carcinoma. Int J Oncol 46:607-18
Bender, David; Sill, Michael W; Lankes, Heather A et al. (2015) A phase II evaluation of cediranib in the treatment of recurrent or persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol 138:507-12
Powell, Matthew A; Sill, Michael W; Goodfellow, Paul J et al. (2014) A phase II trial of brivanib in recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study. Gynecol Oncol 135:38-43

Showing the most recent 10 out of 59 publications