New treatment strategies are desperately needed for treating skeletal malignancy. Skeletal malignancies can be either primary cancer that originated in the bone, such as osteosarcoma, or metastatic cancer that spread from another organ to the skeleton, as in the case of breast or prostate cancer. In this thesis, I will detail two projects that focus on the discovery of new treatment strategies for both primary skeletal malignancy and metastatic skeletal malignancy.
The first project focuses on the primary skeletal malignancy, osteosarcoma, a rare cancer that is commonly diagnosed in children and young adults and metastasizes to the lungs. The survival rate for lung metastatic patients is dismal and has not improved in the decades since the approval of combination chemotherapeutics for treatment. Our recent work shows that targeting the epigenetic changes is effective in treating osteosarcoma as well as the resulting lung metastases. Using preclinical mouse models, using FDA approved pan-histone deacetylase (HDAC) inhibitors panobinostat and romidepsin we can significantly reduce the growth of primary osteosarcoma the resultant lung metastases as well as prevent the formation of these metastases. We propose that HDAC inhibition of HDACs could be effective in treating patients with primary and lung metastatic osteosarcoma.
The second project focuses on metastatic prostate cancer. By investigating the interactions of bone resident mesenchymal stem cells (MSCs) and prostate cancer cells, we discovered that secreted factors from the MSCs, including interleukin 28 (IL-28), promote the evolution of apoptotic resistant prostate cancer cells. The signal transducer and activator of transcription proteins (STAT) signaling pathway in these MSC educated prostate cancer cells becomes altered making them sensitive to STAT3 inhibition. Treatment both in vitro and in vivo with the small molecule STAT3 inhibitor, S3I-201 effectively kills the apoptotic resistant prostate cancer cells. We propose that prostate cancer cells are selected by MSCs in the bone microenvironment to become resistant to chemotherapies (e.g., docetaxel) while at the same time become more sensitive to STAT3 inhibition. Based on these findings, we believe that targeting STAT3 signaling is a therapeutic option for men with incurable bone metastatic prostate cancer.
|Advisor:||Lynch, Conor C.|
|Commitee:||Lau, Eric, Monteiro, Alvaro, Reed, Damon|
|School:||University of South Florida|
|Department:||Biology (Cell Biology, Microbiology, Molecular Biology)|
|School Location:||United States -- Florida|
|Source:||DAI-B 82/2(E), Dissertation Abstracts International|
|Subjects:||Oncology, Cellular biology, Molecular biology|
|Keywords:||Histone deacetylase, Interleukin 28, Mesenchymal stem cell, Osteosarcoma, Prostate cancer|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be