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. To improve patient outcomes, we must identify the appropriate molecularly targeted agents to combine with chemotherapy, a concept we term molecularly enhanced chemotherapy. Such combinations must be based upon a mechanistic understanding of tumor cell vulnerabilities which can be exploited to create synergism and synthetic lethality. Our objective in this renewal application is to capitalize on the most common mutation in high-risk endometrial cancers, p53, to design new and more active combinatorial regimens that can improve response in the upfront setting. p53 mutations alter the master regulators of cell cycle checkpoints in predictable yet distinct ways which can be capitalized upon to overcome resistance to chemotherapy using targeted agents that block compensatory survival pathways. Therefore, our central hypothesis is that molecular inhibitors of key master regulators, chosen based upon the knowledge of the p53 mutational status, synergize with chemotherapy and promote catastrophic tumor cell death. We term this concept molecularly enhanced chemotherapy.
In Specific Aim #1, we will determine the role of p53, other cell cycle checkpoint controllers and angiogenic markers as predictors of sensitivity when anti-angiogenic molecular inhibitors are combined with chemotherapy.
This aim i ncorporates clinical specimens from a completed trial, GOG/NRG 86P, the first national study to combine molecular inhibitors with chemotherapy for advanced/recurrent endometrial cancer.
In Specific Aim #2, we will assess the mechanisms of resistance to therapy as defined by outcomes from NRG/GOG 86P and identify alternative molecularly enhanced combinations.
In Specific Aim #3, we will interrogate the function of p53 mutations that are variants of unknown significance (VUS) to define the best therapy for these tumors. The major goal of this aim is to bin VUS from NRG/GOG 86P into functional categories and understand the impact of recurrent VUS on cell transcription and cell cycle regulation. At the completion of these studies, it is our expectation that we will have designed and tested synergistic drug combinations tailored for specific endometrial cancer subtypes. These studies will make a significant positive impact on the field by enhancing the design and choice of therapy for future endometrial cancer 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 begins a retrospective analysis of specimens from a clinical trial in advanced endometrial tumors to examine synthetic lethality through the use of molecularly enhanced chemotherapy. The translational studies are anticipated to identify which endometrial tumor subtypes are associated with response to molecularly enhanced therapy and define novel approaches to overcome resistance, thereby significant impacting the design of future endometrial cancer treatment regimens.
|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|
|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; 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|
|Dai, Donghai; Thiel, Kristina W; Salinas, Erin A et al. (2016) Stratification of endometrioid endometrial cancer patients into risk levels using somatic mutations. Gynecol Oncol 142:150-157|
|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|
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