Graduation Year

2020

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Biology (Cell Biology, Microbiology, Molecular Biology)

Major Professor

Conor C. Lynch, Ph.D.

Committee Member

Eric Lau, Ph.D.

Committee Member

Alvaro Monteiro, Ph.D.

Committee Member

Damon Reed, M.D.

Keywords

histone deacetylase, interleukin 28, mesenchymal stem cell, osteosarcoma, prostate cancer

Abstract

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.

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