Indiana University-Purdue University Indianapolis (IUPUI) / Despite therapeutic advancements, prostate cancer remains the second
most common cause of cancer-related mortality in men. Docetaxel is the first
cytotoxic agent to show modest improvements in overall survival rate in patients
with metastatic prostate cancer. Unfortunately, over half of these patients do not
respond to treatment and ultimately all develop resistance. The mechanism
mediating docetaxel resistance remains unknown. Survivin has a classical
biological role in cancer, in fact survivin has been shown to be overexpressed in
almost every solid tumor and is associated with drug resistance and clinically
aggressive disease. In these studies I demonstrate that docetaxel resistant cells
have overexpression of survivin compared to sensitive parental cells, knockdown
of survivin decreases docetaxel resistance, and stable overexpression of survivin
increases resistance to docetaxel. The data in these studies suggest that survivin
is likely implicated in docetaxel resistance and treatment with a direct survivin
inhibitor may sensitize resistant cells to docetaxel. To this end the evaluation and
optimization of two different backbones of survivin inhibitors was performed. One
such inhibitor identified is LQZ-7-3 which decreases survivin level via
proteasome degradation, leads to apoptosis of cells, and showed efficacy in a
prostate cancer xenograft model in vivo when given in an oral formulation. LQZ-
7-3 showed strong specificity to survivin versus other IAP family members at the
protein level. Another inhibitor, LQZ-7F-1, demonstrated nanomolar inhibition of cancer cell growth and similar effects on survivin. Both compounds synergized
with docetaxel in vitro warranting future in vivo efficacy studies as a combinatorial
therapy. Overall, our findings indicate survivin is a significant contributor to
docetaxel resistance in metastatic prostate cancer at the molecular level and
survivin inhibitors may prove efficacious as a new therapy to sensitize cancer
cells to chemotherapies.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/21993 |
| Date | 01 1900 |
| Creators | Peery, Robert Craig |
| Contributors | Jerde, Travis, Zhang, Jian-Ting, Pili, Roberto, Safa, Ahmad, Sullivan, William |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
Page generated in 0.002 seconds