Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Biomedical Sciences

First Advisor's Name

Jeremy W. Chambers

First Advisor's Committee Title

Committee chair

Second Advisor's Name

Fenfei Leng

Second Advisor's Committee Title

Committee member

Third Advisor's Name

Helen Tempest

Third Advisor's Committee Title

Committee member

Fourth Advisor's Name

Dietrich Lorke

Fourth Advisor's Committee Title

Committee member

Keywords

Sab, Ovarian cancer, mitochondria, Chemotherapy, drug resistant

Date of Defense

3-29-2018

Abstract

The American Cancer Society predicts there will be 110,070 new cases and 32,120 deaths due to gynecological malignancies in 2018. A major contributing factor to the high mortality associated with gynecological cancers is the recurrence of treatment-resistant tumors. Ovarian cancer (OC) remains the most lethal gynecological malignancy, yet the mechanisms responsible for regulating tumor resistance and vulnerability are largely unknown or undruggable. Therefore, the goal of this research is to identify mechanisms responsible for therapeutic resistance in gynecological cancers and discover innovative approaches to circumvent these molecular alterations. Our efforts began in OC where secondary analysis of gene expression data from OC studies revealed that Sab, an outer mitochondrial membrane (OMM) scaffold protein, was down-regulated in OC tumors compared to normal tissue controls. Our previous studies demonstrate that Sab-mediated OMM signaling induces cell death in cervical cancer. In the current study, we found that Sab concentrations corresponded to chemoresponsiveness in a panel of OC cells; wherein, OC cells with low Sab levels were chemo resistant. Dynamic BH3 profiling revealed that cells with high Sab expression were primed for apoptosis. Furthermore, over-expression of Sab in chemo resistant cells enhanced apoptotic priming and restored cellular vulnerability to cisplatin/paclitaxel treatment. Additionally, an examination of treatment-resistant metastatic uterine cancer (UC) cells were found to have low Sab concentrations compared to vulnerable primary site-derived UC cells. Ectopic expression of Sab in chemo resistant UC cells enhanced the susceptibility towards megestrol acetate and BH3-mimetic ABT-737. To exploit the relationship between Sab concentrations and chemo-responsiveness in gynecological cancer cells, we developed a high-throughput screening assay to detect Sab levels in chemo-resistant OC cells. In collaboration with the Torrey Pines Institute for molecular studies, we have identified compounds that can increase Sab levels in resistant OC cells. The identified compounds improved the effectiveness of cisplatin/paclitaxel therapy. We propose that Sab may be a prognostic marker to discern personalized treatments for gynecological cancer patients. Furthermore, pharmacologically enhancing Sab-mediated signaling may increase the efficacy of chemotherapeutic agents, which would mean lower doses that would limit toxic side-effects.

Identifier

FIDC006535

Available for download on Saturday, March 09, 2019

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