Cellular resistance is one of the major causes of therapeutic failure for solid tumors, thus highlighting the need to identify novel factors driving aggressive phenotypes. Overexpression of metadherin (MTDH, also known as AEG-1 and LYRIC) has been documented in numerous solid tumors to date and correlates with poor prognosis. Moreover, MTDH overexpression has been implicated in metastasis and resistance to therapy, two important hallmarks of an aggressive cancer. We recently made the important discovery that MTDH acts as an RNA binding protein to alter translation of multiple mRNAs, thus identifying a potential role for MTDH in post- translational gene expression. These mRNAs include several DNA repair proteins in the Fanconi anemia (FA) pathway. Our objective in this application is to determine the role of MTDH regulation of DNA repair in resistance to therapy. The rationale for this project is that because MTDH is highly expressed in multiple cancer types and contributes to the emergence of a resistant phenotype, mechanistic insights into how MTDH functions will offer a strong scientific framework whereby MTDH pathway targeted therapies can be developed. To test our central hypothesis, we propose three specific aims:
In Aim 1, we will identify mechanisms by which MTDH association with specific mRNAs alters the DNA damage response pathway. Using MTDH-deficient cancer cell lines and MTDH-/- mouse embryonic fibroblasts, we will study the role of MTDH in mRNA metabolism and control of translation of Rad18, FANCI, FANCD2 and other DNA repair proteins. We will extend studies to determine if MTDH knockdown or disruption the MTDH:mRNA complex by mRNA mimetics are sufficient to perturb MTDH translational regulation of FA pathway genes.
In Aim 2, we will overcome resistance to cisplatin by targeting MTDH and the DNA repair pathway. We will evaluate whether targeting MTDH and the FA DNA repair pathway can increase the therapeutic efficacy of cisplatin via disruption of the cellular response to DNA damage.
In Aim 3, we will determine the effect of MTDH expression and FA pathway activation on resistance to ICL-inducing agents in cancer. Studies will include 1) xenograft experiments using well-characterized human endometrial tumors from our viable tumor bank; and 2) immunohistochemical analysis of the MTDH and FA pathway in FFPE tumor tissues from 86 advanced endometrial cancer patients treated with ICL-inducing agents. Upon the successful completion of the proposed research, it is our expectation that we will understand the pathological function of MTDH through its regulation of mRNA stability and translation of FA pathway proteins. These results are expected to have an important positive impact because they will provide a strong mechanistic basis for the correlation of MTDH overexpression with therapeutic resistance and serve as a foundation for the future development of MTDH-targeted therapies.
MTDH is an oncogene involved in both metastasis and drug resistance, the most deadly aspects of cancer and drivers of therapeutic failure. Improvements in cancer treatment rely on advances in the molecular understanding of drug resistance, including how cells can repair damaged DNA after treatment with chemotherapy. By providing novel insights into the role of MTDH in the enhancement of DNA repair, we will facilitate the translation of basic biomedical research into clinical therapeutics.
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|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|
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|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|
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|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|
|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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