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.
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.
|Reyes, Henry D; Thiel, Kristina W; Carlson, Matthew J et al. (2014) Comprehensive profiling of EGFR/HER receptors for personalized treatment of gynecologic cancers. Mol Diagn Ther 18:137-51|
|Brachova, Pavla; Mueting, Samuel R; Devor, Eric J et al. (2014) Oncomorphic TP53 Mutations in Gynecologic Cancers Lose the Normal Protein:Protein Interactions with the microRNA Microprocessing Complex. J Cancer Ther 5:506-516|
|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|
|Fleming, Gini F; Filiaci, Virginia L; Marzullo, Brandon et al. (2014) Temsirolimus with or without megestrol acetate and tamoxifen for endometrial cancer: a gynecologic oncology group study. Gynecol Oncol 132:585-92|
|Brachova, Pavla; Thiel, Kristina W; Leslie, Kimberly K (2013) The consequence of oncomorphic TP53 mutations in ovarian cancer. Int J Mol Sci 14:19257-75|
|Meng, Xiangbing; Thiel, Kristina W; Leslie, Kimberly K (2013) Drug resistance mediated by AEG-1/MTDH/LYRIC. Adv Cancer Res 120:135-57|
|Meng, Xiangbing; Laidler, Laura L; Kosmacek, Elizabeth A et al. (2013) Induction of mitotic cell death by overriding G2/M checkpoint in endometrial cancer cells with non-functional p53. Gynecol Oncol 128:461-9|
|Meng, Xiangbing; Zhu, Danlin; Yang, Shujie et al. (2012) Cytoplasmic Metadherin (MTDH) provides survival advantage under conditions of stress by acting as RNA-binding protein. J Biol Chem 287:4485-91|
|Garcia, Agustin A; Sill, Michael W; Lankes, Heather A et al. (2012) A phase II evaluation of lapatinib in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: a gynecologic oncology group study. Gynecol Oncol 124:569-74|
|Yang, Shujie; Thiel, Kristina W; De Geest, Koenraad et al. (2011) Endometrial cancer: reviving progesterone therapy in the molecular age. Discov Med 12:205-12|
Showing the most recent 10 out of 29 publications