The AACR-FNAB Fellows Grant for Translational Pancreatic Cancer Research provides funding to allow a meritorious young investigator to pursue an independent line of investigation within the context of his/her current fellowship placement. This grant provides a “bridge” between a training and an independent position, offering an opportunity for a young investigator to develop a new direction for his/her research program that otherwise may not have been possible in the absence of this funding.
2011 GRANTEE
Xiaoqun Dong, M.D., Ph.D.Postdoctoral Fellow, UT MD Anderson Cancer Center, Houston, TX
NR5A2/LRH1 as a Potential Therapeutic Target of Pancreatic Cancer
"Genome-wide association study has identified NR5A2 (nuclear receptor subfamily 5 group A member 2)/LRH1 (liver receptor homolog 1) gene as a susceptibility factor for pancreatic cancer. LRH1, a direct target of PDX1, governs liver and pancreas differentiation in early embryonic development and controls cholesterol/bile-acid homeostasis and steroidogenesis in adulthood. LRH1 plays a role in the development of colon and breast cancer by functionally interacting with β-catenin/Tcf4 signaling pathway and by stimulating the estrogen metabolic genes. However, the role of LRH1 in pancreatic cancer development/progression is unknown. We have preliminary data suggesting that LRH1 is overexpressed in pancreatic tumors and LRH1 genotypes may correlate with tumor characteristics and overall survival of pancreatic cancer. To demonstrate whether LRH1 can be a novel therapeutic target for the treatment of pancreatic cancer, I hypothesize that LRH1 overexpression/genotype predicts worse clinical outcome and aggressive tumor characteristics of pancreatic cancer. I will determine the LRH1 genotype and measure LRH1 protein and mRNA expression levels in pancreatic tumors and correlate to the pathological characteristics of the tumor and overall survival of the patients. I will demonstrate the functional significance of the LRH1 gene variants that are significantly associated with the clinical outcome or tumor characteristics. Finally, I will investigate whether knockdown the LRH1 gene in pancreatic cancer cell lines by siRNA will inhibit tumor growth. The results will provide important information on the role of LRH1 in pancreatic cancer development and progression. It will generate the scientific rationale for LRH1 as a novel therapeutic target in the treatment of pancreatic cancer. The biomarkers will be useful in selecting patients who are most likely to benefit from LRH1-targeted therapy."
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2010 GRANTEE
Amy L. Collins, M.D.Clinical Instructor House Staff, The Ohio State University, Columbus, OH
The Role of Stellate Cells on MicroRNA Expression in Pancreatic Cancer
"Pancreatic cancer’s inherent resistance to chemotherapy and radiation make it one of the deadliest malignancies. In pancreatic tumors, cancer cells have gained the ability to survive in unfavorable conditions such as hypoxia, a low-oxygen state. It is becoming obvious that pancreatic cancer cells are not solely responsible for altering the local tumor microenvironment to make conditions more favorable for growth and invasion. In fact, they appear to rely on input from nearby helper cells, such as pancreatic stellate cells (PSCs), perhaps through their effect on small genes called microRNAs (miRs). We have shown that pancreatic cancer has a unique expression pattern of microRNAs and that several of these microRNAs are associated with hypoxia. My project plans to elucidate the role of PSCs in regulating microRNA expression and characteristics of pancreatic cancer. We plan to harvest and culture PSCs from fresh human pancreatic tissue specimens obtained from patients undergoing surgery for pancreatic cancer. By culturing PSCs together with pancreatic cancer cells, we will determine the impact of PSCs on pancreatic cancer cell microRNA expression patterns. We will determine if changes in pancreatic cancer cell miR-21 (one of the most commonly altered microRNAs) expression levels induced by PSCs allow the pancreatic cancer cell to survive in a low- oxygen environment. Similarly, we will determine if this survival advantage can be imparted upon normal and precancerous pancreatic cells.
"This is the first project of its kind to look at obtaining PSCs from humans and analyzing microRNA. This project could give an explanation as to how the microenvironment affects pancreatic cancer cells as evidenced by changes in microRNAs. With these answers, we can better understand how stellate cells function to support pancreatic cancer cells in an otherwise hostile environment allowing researchers to move forward with novel treatment strategies in the future.
"I am honored by and grateful for the generous support provided by the AACR–FNAB Fellows Grant for Translational Pancreatic Cancer Research which provides significant support for this project and I would like to thank my mentor Dr. Mark Bloomston, who has been an excellent role-model and continues to help my development as a cancer researcher."
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