Mc Millan Ching

Participant: PROMISE AGEP Research Symposium

Mc Millan Nicol Ching

Department: Oncology

Institution: University of Maryland Baltimore (UMB)

 

2018 ABSTRACT

Functional analysis of PGE₂ pathway members MRP4 and EP4 in Ovarian Cancer

Mc Millan Ching, Cong (Ava) Fan, Dana Roque, Gautam Rao, Paul Staats, Amy Fulton, Jocelyn Reader

¹Department of Oncology, ²Division of Obstetrics-Gynecology & Reproductive Science, ³Department of Pathology, ⁴Marlene and Stewart Greenebaum Comprehensive Cancer Center, ⁵University of Maryland School of Medicine , ⁶Baltimore Veterans Affairs Medical Center, University of Maryland Baltimore, Baltimore, MD

Ovarian cancer is the leading cause of death from gynecologic malignancy in the United States. Most cases of ovarian cancer present in late stages lead to recurrent disease which is incurable and often fatal due to chemoresistance. Cyclooygenases, COX-1 and COX-2, are enzymes that catalyze the production of the prostaglandin E2 (PGE₂), a lipid mediator that is functionally linked to progression of many cancers including ovarian cancer. PGE₂ is exported from the cell via multidrug resistance-associated protein 4 (MRP4) where it acts in a paracrine and autocrine manner by activating a family of four G-protein coupled receptors (EP1-4) that are linked to different intracellular signaling pathways. COX-1 and COX-2 have been shown to be overexpressed in primary ovarian cancer as well as in many ovarian cancer cell lines. We hypothesized that the EP4 receptor is overexpressed in ovarian cancer and that binding of its cognate ligand, PGE₂, will drive ovarian cancer progression and that inhibition of the EP4-mediated signaling will lead to inhibition of ovarian cancer growth and metastasis. We also hypothesized that MRP4 will similarly play a role in modulating the amount of PGE₂ in the microenvironment in ovarian cancer; thereby, affecting signaling via of EP4 receptor. To test these hypotheses, we investigated the expression of these PGE2 protein pathway members in primary ovarian cancer and ovarian cancer cell lines. Functional testing of dual EP4/ MRP4 inhibition may provide much needed new therapies for the treatment of ovarian cancer.

 

BIOGRAPHICAL SKETCH

I am Mc Millan Ching, a post-baccalaureate research fellow of the University of Maryland School of Medicine. I am currently investigating the role of PGE₂ pathway members in ovarian cancer. I received my undergraduate degrees in BS Molecular Biosciences and Biotechnology; and BA Philippine Language, Linguistics, and Literature from the University of Hawaii at Manoa. I had previous research interests in HIV co-infection with tropical fungal pathogens, particulary penicillium marneffei, endemic in Southeast Asia, as well as the development of HIV-associated neurological disorders (HAND) in patients living with HIV. I also investigated the regain of function after amniotic stem cell transplantation in spf-ash, an animal model of ornithine transcarbamylase deficiency. My undergraduate thesis centered on the investigation of the peptide transporters involved in the phytosiderapore-mediated transport of iron in higher legumes – Leucaena and Common Beans – in alkaline soil.

 

GENERAL SUMMARY OF GRADUATE RESEARCH

I am currently investigating the role of Prostaglandin E2 (PGE₂) pathway members MRP4 and EP4 as therapeutic targets in ovarian cancer with guidance from Amy Fulton, PhD, and Jocelyn Reader, PhD of the Marlene and Stewart Greenebaum Cancer Center of the University of Maryland Baltimore. We are interested in the PGE₂ pathway members because of the importance of cyclooxygenases, COX-1 and COX-2, as catalysts for the production of PGE₂, which is a lipid mediator that is important in the progression of ovarian cancer. PGE₂ is exported by the cells via multidrug resistance-associated protein 4 (MRP4) where it acts in paracrine and autocrine manner by activating G-protein coupled receptors (EP1-4). EP4 activates PKA/Camp, p13k and ERK pathways, which prompts cancer cells to have uninhibited growth and undergo metastasis. We hypothesized that through gene silencing and antagonist-mediated blocking, disruption of MRP4 or EP4 export and recognition of PGE₂, respectively, should inhibit ovarian cancer growth and metastasis in tumor microenvironment. Ovarian primary cancer cells and cell lines overexpress COX-1, COX-2, EP4, and MRP4. We are currently using different EP4 antagonists to investigate how inhibition of EP4 receptor affects proliferation, stem-like phenotype, and metastasis. While we examine drug sensitivity of high grade serous (HGS) cancer cell lines to chemotherapeutic substrates of MRP4. We also do dual-drug assays to see the combined effects of MRP4 substrates and EP4 antagonists to ovarian cancer. We previously looked at the %positivity of markers for stem-like phenotypes present In HGS cell lines via flow cytometry. We plan to transform HGS cell lines into spheroids and compare their stem-like marker expression prior to transformation.

 

SELECTED LIST OF PRESENTATIONS AND PUBLICATIONS

1. Ching, M., Pruksaphon, K., Dankai, W., and Youngchim, S. Time-dependent morphological determination of dimorphic Penicillium marneffei by the expression of yeast-phase antigen in in vitro and In-THP-1 cell cultures line. Mānoa Horizons Journal, University of Hawai’i at Mānoa Honolulu, HI. Online content (Published: June 8, 2016).
2. Ching, M., Reader, J., Fan, C., Roque, D., Rao, G., and Fulton, A. Functional analysis of PGE2 pathway members MRP4 and EP4 in ovarian cancer. American Association for Cancer Research (AACR): Critical Questions in Ovarian Cancer. Pittsburgh, PA (October 1-5, 2017)
3. Ching, M. and Borthakur, D. Mimosine-Fe(III) Peptide Transporters in Leucaena leucocephala. American Association for the Advancement of Science (AAAS) Annual Meeting. Boston, MA (February 16-20, 2017).
4. Ching, M. and Miki, T. Effects of transplanted human amniotic epithelial cells on enzyme correction and phenotype improvement in spf/ash mouse, an animal model of ornithine transcarbamylase deficiency. ABRCMS, Tampa, FL (November 9-12, 2016).
5. Ching, M., Wang, H., Otoshi, C. and Chang, L. DTI changes in corpus callosum after 1 month of CogMed working memory training in HIV patient. Queen’s Medical Center Summer Internship Program Presentations. Honolulu, HI. Poster presentation (August 5, 2016).