Candidate: My immediate career goals are to obtain the necessary training and skill set required to be competitive for a tenured faculty position and to accumulate data sufficient for an R01 or similar funding mechanism. My long term career goals are to be a tenured, funded cancer biology professor, a mentor, and a science administrator. To this end, the key elements of my career plan are focused on 1) developing my independent research, 2) continuing my technical and research administrative education, 3) honing my communication skills, and 4) gaining more mentoring experience. Environment: I can successfully meet my goals because I have access to state-of-the-art equipment, core facilities, and educational resources at Rice University, the Texas Medical Center, and through a prostate cancer P01 collaboration that includes the University of Delaware, Emory University, and Cedars-Sinai. I also have a team of phenomenal mentors who are leaders in the prostate cancer and cancer health disparities fields. These mentors include my primary mentor, Dr. Mary Farach-Carson, co-mentor, Dr. Leland Chung, and Drs. Nora Navone and Lovell Jones, who have each agreed to provide me with career development guidance. Research: Prostate cancer (PCa) is the second leading cause of death in North American men, where 80% of PCa mortality is due to bone metastasis. PCa tumors can contain neuronal-like neuroendocrine (NE) PCa cells, which correlates with poor prognosis. NE PCa cells are resistant to apoptosis, secrete proteins to induce cell proliferation and angiogenesis, and can de-differentiate to contribute to tumor growth. Our lab recently published data revealing that bone marrow stromal cell (BMSC) paracrine signaling induces apoptosis in co-cultured bone metastatic PCa cells. However, a subpopulation of the bone metastatic PCa cells can avoid cell death and undergo neuroendocrine differentiation (NED). One process that has been shown to mediate cancer cell survival and cell differentiation is autophagy, the homeostatic process of intracellular degradation and recycling. Thus, I propose that autophagy is a cytoprotective mechanism that PCa cells use to survive and undergo NED in the bone marrow stromal microenvironment. To address my hypothesis, I will (1) dissect autophagy regulation in PCa cells exposed to BMSC, (2) demonstrate that autophagy enhances PCa cell survival and promotes NED, and (3) show that autophagy attenuation increases PCa cell death. Autophagy induction and function will be analyzed using immuno-blot and -staining for autophagy markers, such as LC3, and using acidic vesicle dyes, such as monodansylcadaverin. PCa cells will be subjected to genetic and pharmacological autophagy modulation and assayed for cell viability and the NED phenotype. My investigation will identify pathways to attenuate autophagy and redirect bone metastatic PCa cells towards cell death.

Public Health Relevance

Prostate cancer (PCa) bone metastasis is responsible for 80% of PCa death. Therefore, it is imperative to understand the biology of bone metastatic PCa cells in the bone environment. Hence, the purpose of this project is to determine the role of autophagy, a homeostatic process, in bone metastatic PCa cell survival and to determine if inhibition of autophagy can kill bone metastatic PCa cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Scientist Development Award - Research & Training (K01)
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Subcommittee G - Education (NCI)
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Ojeifo, John O
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Rice University
Schools of Arts and Sciences
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Chang, Megan A; Morgado, Micaela; Warren, Curtis R et al. (2014) p62/SQSTM1 is required for cell survival of apoptosis-resistant bone metastatic prostate cancer cell lines. Prostate 74:149-63
Chang, M A; Patel, V; Gwede, M et al. (2014) IL-1? induces p62/SQSTM1 and represses androgen receptor expression in prostate cancer cells. J Cell Biochem 115:2188-97