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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA099908-13
Application #
8840817
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Forry, Suzanne L
Project Start
2002-07-17
Project End
2018-04-30
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
13
Fiscal Year
2015
Total Cost
$252,448
Indirect Cost
$85,264
Name
University of Iowa
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52246
Devor, Eric J; Cha, Elizabeth; Warrier, Akshaya et al. (2018) The miR-503 cluster is coordinately under-expressed in endometrial endometrioid adenocarcinoma and targets many oncogenes, cell cycle genes, DNA repair genes and chemotherapy response genes. Onco Targets Ther 11:7205-7211
Ebeid, Kareem; Meng, Xiangbing; Thiel, Kristina W et al. (2018) Synthetically lethal nanoparticles for treatment of endometrial cancer. Nat Nanotechnol 13:72-81
Devor, Eric J; Miecznikowski, Jeffrey; Schickling, Brandon M et al. (2017) Dysregulation of miR-181c expression influences recurrence of endometrial endometrioid adenocarcinoma by modulating NOTCH2 expression: An NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol 147:648-653
Devor, Eric J; Reyes, Henry D; Gonzalez-Bosquet, Jesus et al. (2017) Placenta-Specific Protein 1 Expression in Human Papillomavirus 16/18-Positive Cervical Cancers Is Associated With Tumor Histology. Int J Gynecol Cancer 27:784-790
Li, Yujun; Gonzalez Bosquet, Jesus; Yang, Shujie et al. (2017) Role of metadherin in estrogen-regulated gene expression. Int J Mol Med 40:303-310
Devor, Eric J; Gonzalez-Bosquet, Jesus; Warrier, Akshaya et al. (2017) p53 mutation status is a primary determinant of placenta-specific protein 1 expression in serous ovarian cancers. Int J Oncol 50:1721-1728
Reyes, Henry D; Miecznikowski, Jeffrey; Gonzalez-Bosquet, Jesus et al. (2017) High stathmin expression is a marker for poor clinical outcome in endometrial cancer: An NRG oncology group/gynecologic oncology group study. Gynecol Oncol 146:247-253
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
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

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