Unveiling the Role of Nuclear Export Protein 1 (XPO1)-microRNA Axis in Gastric Cancer
Abstract
The goals of the Principal Investigator (PI) are to have a long-term independent research career in translational cancer research. Work done on this Department of Defense (DoD)-funded project will enhance the PIs skillset through training in innovative translational research methodologies. The PI will gain training in molecular biology, high-throughput non-coding RNA analyses, patient derived models, biomarker assessment methodologies, and epidemiology-based research. The PI has assembled experts to help her achieve the said goals. Her training supported by the DoD Peer Reviewed Cancer Research Program Horizon Award will help her complete her PhD thesis and launch her successful research career. To achieve these training goals, the PI has choses a highly translational project that could potentially bring forward a novel therapy for gastric cancer patients. Gastric cancer remains a deadly disease that affects the lives of civilians and military personnel equally. Despite significant advancements in early detection methods and the development of novel molecularly driven treatments for early stage gastric cancer, the 5-year survival of patients with metastatic disease remains at around 20%. There is an urgent need for the identification of newer and more effective treatments for this deadly disease. The PI has identified that nuclear exporter protein Exportin 1 (XPO1) is over-expressed and is necessary for gastric cancer proliferation and survival. Nuclear protein transport (both import and export) is governed by a set of proteins termed Karyopherins that spatially regulates the function of important tumor suppressor and genome surveillance proteins. However, unusual export of proteins through XPO1 (a Karyopherin) disturbs this balance leading to tumor suppressor protein inactivation. The PI has demonstrated that blocking XPO1 by specific inhibitor of nuclear export (SINE) selinexor retains tumor suppressor proteins in the cell nucleus and suppresses gastric cancer growth in vitro and in vivo. Selinexor recently received Food and Drug Administration approval for the treatment multiple myeloma and is being investigated in a variety of pre-clinical and clinical studies in solid tumors and hematological malignancies. More importantly, SINE compounds were found to synergize with standard of care agents and enhance the anti-tumor potential of several chemotherapies in gastric cancer cell lines and xenograft models. Besides protein nuclear retention, the preliminary studies done by the PI show that XPO1 inhibition can also regulate the expression of gastric cancer promoting non-coding RNAs (microRNAs and PIWI RNAs). These new findings for the first time highlight the role of XPO1 in non-coding RNA biology in gastric cancer. The PI proposes to leverage these findings to identify biomarkers of therapy response or resistance to XPO1 inhibitors that could benefit patient selection in the clinic. In Aim 1, studies are proposed to compare whether XPO1 expression differences have link to overall survival between African American and White American patient population. Although both demographics have overexpression of XPO1, if one group has higher overexpression linked to poorer overall survival it would be beneficial to explore SINE efficacy within this patient population first. The purpose of Aim 2 is to lock down a blood based non-coding RNA pharmacodynamics marker. This would help develop a less invasive screening method to monitor patient responses over time. Long term, the PI will collaborate with Phase I clinicians to help design a protocol for immediate implementation of the findings from this proposal in gastric cancer patients. These assertions are supported by the track record of the mentor, who has moved at least two laboratory projects on selinexor into clinical studies. The completion of this proposal is anticipated to bring a new treatment option for gastric cancer patients. The research development plan will support the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010704
Entities
People
- Rachel Sexton
Organizations
- United States Army
- Wayne State University