2022 Mentored Investigator Grant Recipient — Pamela Rojas de Santiago, PhD
Pamela Rojas de Santiago, PhD
University of Pennsylvania
Investigating the Therapeutic Potential of CRABP2 in HGSOC
Project Summary
Ovarian cancer remains a leading cause of cancer-related mortality in developed countries, accounting for approximately 180,000 deaths worldwide annually. Ovarian cancer is a heterogeneous disease and the most common subtype is high-grade serous ovarian carcinoma (HGSOC). Most patients with HGSOC present to care with advanced disease, at which point prolonged remissions after primary therapy are rare, and recurrences are marked by increasing chemoresistance. The lack of effective treatments represents a persistent unmet medical need. Therefore, it is important to understand the molecular mechanisms that drive aggressive tumor growth and to develop effective therapies based on their molecular signature. Previous work in our laboratory identified Cellular Retinoic Acid Binding Protein 2 (CRABP2) as one of the most differentially expressed proteins between tissue interstitial fluid from normal fallopian tube epithelium and matched HGSOC. The main function of CRABP2 is to transfer retinoic acid (RA) from the cytoplasm to the RA receptors in the nucleus, which leads to the expression of a wide range of genes related to cell differentiation and apoptosis. In cancer, the RA/CRABP2 pathway has been widely associated with tumor suppression. Further assessment showed that CRABP2 expression is binary, with robust expression in HGSOC tissues and absent expression in benign fallopian tube. Interestingly, higher CRABP2 expression correlates with a reduction in both the overall and the progression-free survival in HGSOC patients. Surprisingly, we found that the CRABP2 loss in tumor cells produced a profound reduction in cell viability. This is in contrast to the expected anti-tumor activity previously associated with CRABP2. Because CRABP2 function has not been explored in ovarian cancer, we propose to characterize the suggested pro-oncogenic function of CRABP2 in ovarian carcinoma. We hypothesize that CRABP2 is not transferring RA from the cytoplasm to the nucleus, thus, the tumor-suppressor activities of RA/CRABP2 are not being activated. Moreover, we propose that CRABP2 is driving a non-canonical pro-tumorigenic pathway in HGSOC. We will quantify the RNA and protein levels and will assess the localization of the main components of the pathway to identify if they are available and functional in HGSOC cells in presence or absence of RA. This will help us to determine the mechanism behind CRABP2 in HGSOC. Moreover, we will study how CRABP2 loss in tumor cells injected in mice affects tumor growth. Our study aims to identify if CRABP2/RA is a novel druggable pathway in ovarian carcinoma that may provide a new therapeutic opportunity for patients.
Bio
Dr. Pamela Rojas de Santiago is currently a postdoctoral researcher with the Ovarian Cancer Research Center at the University of Pennsylvania. Pamela obtained her undergraduate degree in Biology from Pontificia Universidad Catolica de Chile. Her Masters in Biological Sciences and Ph.D. in Cell and Molecular Biology degrees were obtained from the same Institution. During her Ph.D. training, Pamela focused on the role of the RNA-editing enzyme, ADAR1, in breast cancer.
In 2020, Pamela joined Dr. Ronny Drapkin’s laboratory at the University of Pennsylvania. Here, her research is mainly focused on understanding the role of Cellular Retinoic Acid Binding Protein 2 (CRABP2) in ovarian cancer. The Ovarian Cancer Research Alliance Ann and Sol Schreiber Mentored Investigator Award will support Dr. Rojas de Santiago in her studies regarding CRABP2 molecular mechanisms associated with cell survival and apoptosis in high-grade ovarian cancer (HGSOC). Her ultimate goal is to find a therapeutic potential for CRABP2 in HGSOC.