Ovarian cancer is the most lethal gynecological malignancy. In 2016 there will be 22,280 new cases of ovarian cancer and 14,250 deaths. Development of targeted therapies is hindered by the limited understanding of the molecular alterations that occur in early lesions and the ambiguity surrounding the cell of origin of ovarian cancer. Historically, the ovarian surface epithelium was believed to be the site of ovarian cancer progenitor cells, but recent evidence suggests that the fallopian tube epithelium is also a progenitor site. PAX8 is expressed in 80-96% of all high grade serous ovarian cancer (HGSOC) tumors as well as in tissues of Mllerian origin, including the fallopian tube. While PAX8 is not expressed in the ovary, malignant transformation of the ovary in mouse models leads to PAX8 acquisition. Knockdown of PAX8 in HGSOC tumors leads to apoptosis, suggesting that it may provide a universal target regardless of cell of origin. The objective of this research project is to validate key pathways downstream of PAX8 in ovarian cancer progression that can be targeted for clinical therapies. We have previously shown that PAX8 regulates the FOXM1 pathway, an oncogene highly expressed in HGSOC. Transcriptomic and proteomic data suggest PAX8 may also regulate focal adhesion, a key pathway in cell migration and metastasis. Therefore, we hypothesize that PAX8 regulates cell migration, growth, and survival of HGSOC and that blocking its expression with the small molecule thiostrepton may provide a multi-pronged therapeutic strategy for targeting tumor cells. Using cells from the fallopian tube, ovarian surface, and HGSOC tumors, Aim 1 will interrogate the cell specific function of PAX8 on cell migration.
Aim 2 will investigate thiostrepton as a HGSOC therapeutic that reduces PAX8 protein. Thiostrepton is an FDA approved natural product derived from streptomycetes that is used clinically to treat bacterial infections in cats and dogs. Our preliminary findings indicate thiostrepton reduces the protein stability of PAX8. Completion of this project will enhance our knowledge of the regulatory role for PAX8 in HGSOC and will identify a novel therapeutic compound to reduce PAX8 levels in tumors. Beyond simply learning techniques, the training plan outlined in this grant will help the applicant develop the skills necessary to become an independent physician scientist capable of identifying and answering clinical questions that can be translated into novel therapies. These skills include: critical thinking, scientific writing, data mining, reading scientific literature, presenting research findings, mentoring, and working as a team.
Ovarian cancer is the most lethal gynecological malignancy. PAX8 is a transcription factor expressed in 80-96% of all high grade serous ovarian cancer that is essential for tumor cell survival. The objective of this research project is to validate key pathways downstream of PAX8 in ovarian cancer progression that can be targeted for clinical therapies.
|Hardy, Laura R; Salvi, Amrita; Burdette, Joanna E (2018) UnPAXing the Divergent Roles of PAX2 and PAX8 in High-Grade Serous Ovarian Cancer. Cancers (Basel) 10:|