Research Projects

2019 Project Descriptions

Project One

Title: ​PDAC early detection biomarkers

Wei-Qun Ding, Ph.D.
Associate Professor of Pathology

Title: PDAC early detection biomarkers

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States. The 5-year survival rate for PDAC is extremely low primarily due to a late stage diagnosis. Early detection is key to improving PDAC outcomes. There are no effective circulating biomarkers currently available for early detection of PDAC. Plasma microRNA (miRNA) signatures have been explored as potential biomarkers for this malignancy, but circulating cancer-specific miRNAs are difficult to selectively analyze, owing to the heterogeneous composition of miRNAs in the blood. We propose new approaches to specifically analyze the miRNAs secreted from PDAC cells into the blood to develop sensitive biomarkers for early detection or monitoring of this malignancy. The key to the new approaches relies on capturing and analyzing the miRNA contents of size-restricted and affinity-isolated exosomes from patient plasma. Exosomes are small secretory membrane vesicles that selectively encapsulate cellular miRNAs and proteins, and are abundantly produced by cancer cells and constantly released into the circulation.  We have observed that size-restricted plasma exosomes express significantly higher levels of cancer-associated miRNAs indicative of PDAC.  We hypothesize that PDAC exosome miRNAs can be selectively enriched from the circulation by size-restricted or affinity-based exosome isolation and serve as non-invasive biomarkers for early detection or monitoring of PDAC. In this summer research project we will test the hypothesis by analyzing miRNA expression in size-restricted and affinity-isolated plasma exosomes from PDAC patients and healthy controls. We have established protocols for size-restricted and affinity-based isolation of plasma exosomes. qRT-PCR will be applied to analyze plasma exosome miRNA expression. The plasma exosome miRNA expression will be compared between PDAC patients and health controls.  We anticipate that the results from this work will provide evidence to support the development of plasma exosome miRNA signatures as circulating biomarkers for early detection or monitoring of PDAC.

Project Two

Title: Compensatory survival mechanism in FLT3-ITD+ acute myeloid leukemia

Jerry Wu, Ph.D.
Professor of Pathology
Stephenson Endowed Chair in Cancer Translational Research
405-271-8001, ext 31092

Abstract: Acute myeloid leukemia (AML) is a common hematologic malignancy. Activating FLT3 mutations via internal tandem duplication (ITD) or kinase domain mutations are the most common genetic alterations in AML. Although FLT3 inhibitors have anti-leukemia effects, FLT3 kinase targeted therapy have not led to a cure. FLT3-ITD+ AML patients who responded to the FLT3 inhibitor treatment retained residual FLT3-ITD+ AML initiating/stem cells, which eventually acquired additional mutations resulting in disease progression. The persistence of FLT3-ITD+ myeloid cells in patients undergoing FLT3-targeted therapy is likely due to alternative signaling mechanisms that allow the leukemia initiating cells to survive in the presence of FLT3 inhibitors. AML cells are derived from myeloid progenitor cells. We postulate that myeloid cytokine signaling is a compensatory mechanism protecting FLT3-ITD+ myeloid leukemia initiating cells from FLT3 inhibitors, and that combined inhibition of the shared cell survival pathway by FLT3-ITD and myeloid cytokines will overcome the resistance to FLT3 inhibitors in FLT3-ITD+ leukemia cells. This hypothesis will be tested during the summer research in FLT3-ITD+ myeloid leukemia cells. Target inhibition, cell viability, induction of apoptosis, changes in anti-apoptotic and apoptotic proteins will be measured. Positive outcomes of the study will reveal a mechanism of persisting FLT3-ITD+ leukemia initiating cells in FLT3 inhibitor therapy and identify the targets for eliminating these AML initiating cells.