Epithelial ovarian cancer is the most lethal gynecologic malignancy. Although response to first line chemotherapy usually leads to complete remission, most cases relapse and then are chemoresistant, leading to premature death. We previously reported that CD133+ cells exhibit characteristics of cancer initiating cells (CICs) including the ability to undergo asymmetric division;other groups have since confirmed our findings and have improved the ability to isolate ovarian CICs by using both CD133 and ALDH cell surface markers. CICs comprise a small proportion of cells within a tumor, are able to survive chemotherapy and importantly, are thought to cause disease recurrence, sometimes years later, in part due to their ability to slow metabolism and enter quiescence. Therefore, identifying specific exploitable targets that distinguish these cells and thus increase their vulnerability is a top priority if we hope to extend life expectancy of women with this disease. Analysis of our gene expression microarray data showed that expression of genes containing Hypoxia inducible factor (HIF) response elements was enriched in CD133+ versus CD133- ovarian cancer cell populations (FDR q=0.078). HIF1? functions as part of a key transcription factor complex regulating metabolic pathways and processes in response to oxygen levels, with low oxygen levels tending to inhibit differentiation. Therefore, we hypothesize that CICs exhibit distinct metabolic pathway differences as compared to non-CIC tumor cells and that targeting of CICs based on these differences will alter the ability of CICs to undergo self-renewal. Our long-term objective is to develop novel therapeutic strategies based on metabolic differences to eradicate CIC populations prior to disease recurrence.
Aim 1 of this proposal is to generate metabolic profiles of CIC cells versus non-CIC ovarian cancer cells for over 2,300 known metabolites and 5,200 unnamed compounds and then determine how CICs differ from non-CICs by identifying the specific cellular pathways and components involved. We will then validate the differential abundance of metabolites and determine if the proportion of CICs can be altered by targeting the specific pathways identified using siRNA technology or relevant therapeutic inhibitors.
In Aim 2, we will determine if the CIC / non-CIC ratio in ovarian cancer cells can be altered by modulating HIF1 pathway activity. Successful completion of these aims will greatly increase understanding of how CICs are able to survive chemotherapy and enter into prolonged remission - by altering their metabolism - to later emerge in chemoresistant form during relapse. Identifying relevant pathways and biological targets that elicit this ovarian CIC phenotype offers an unprecedented opportunity to target the cell population ultimately responsible for the high mortality of this disease.
Statement of Relevance to Public Health Epithelial ovarian cancer is a disease that is most commonly diagnosed at an advanced stage. This proposal seeks to elucidate comprehensive metabolic profiles of the small subset of ovarian cancer cells that are responsible for disease recurrence, and identify specific exploitable therapeutic targets based on these profiles that will allow targeting of these cells and help prevent recurrence of the primary cancer. Successful completion of this work will offer an unprecedented opportunity to find specific vulnerabilities that will eventually allow for eradication of the cells ultimately responsible for the high mortality associated with ovarian cancer.