Graduation Year

2014

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Cell Biology, Microbiology and Molecular Biology

Major Professor

W. Douglas Cress, Ph.D.

Committee Member

Srikumar P. Chellappan, Ph.D.

Committee Member

Jin Q. Cheng, M.D., Ph.D.

Committee Member

Eric B. Haura, M.D.

Keywords

CDK, cisplatin, E2F, NSCLC, paclitaxel

Abstract

Lung cancer is the leading cause of cancer-related death and the second most diagnosed cancer in the United States. Unfortunately, many patients either do not have any common mutations for which there are already targetable agents, or they eventually become resistant to these compounds. As such, there is a high demand for new, effective methods of treating this disease as well as predicting patient prognosis and potential benefit from chemotherapy. In this work, numerous strategies for treating lung cancer are explored.

The first method described here is through the use of a pan-early 2 factor (E2F) inhibitor, HLM006474, which is shown to synergize with paclitaxel in non-small cell lung cancer (NSCLC). Next, we explored the creation and utilization of an E2F signature that is prognostic and predictive of early-stage NSCLC patient benefit from adjuvant chemotherapy (ACT). The third project examined possible targets to enhance sensitivity to cisplatin in NSCLC lacking Kirsten rat sarcoma viral oncogene homolog (KRAS) and epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma receptor tyrosine kinase (ALK) fusions (triple-negative), for which cisplatin is one of the few treatment options. These studies led to the identification of a kinase that is overexpressed in NSCLC and whose knockdown sensitizes cells to platinum agents.

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