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.
2012 GRANTEE
Olorunseun O. Ogunwobi, M.D., Ph.D.Postdoctoral Fellow, University of Florida College of Medicine, Gainesville, FL
Mechanisms of Metastasis in Pancreatic Cancer
“Metastasis is the greatest cause of mortality due to cancer. Unfortunately, whilst significant progress has been made in understanding the etiology and progression of many primary cancers, the basis for metastases of cancers generally remains largely unclear. A number of biological concepts have been proposed as potential role-players in cancer metastasis. Two of these are: epithelial-mesenchymal transition (EMT) and the concept of cancer stem cells. Although many in vitro and animal studies have provided some experimental support for these ideas, no human study to date has provided definitive support for these concepts. Moreover, data from some recent animal studies have questioned the usefulness of these concepts in explaining cancer metastasis. It is, therefore, necessary to explore other possible explanations for cancer metastasis. Although research has focused on the biology of cancer cells from the primary tumor and cancer cells from metastatic lesions and there is some data suggesting that circulating cancer cells have increased metastatic potential, nobody knows what actually happens to cancer cells once they escape from their primary site that enables some of them to survive in the immunologically hostile environment in blood and acquire the capability to colonize secondary sites and become metastatic lesions. I hypothesize that viable cancer cells able to circulate in the blood of cancer patients possess important molecular differences from cancer cells at the primary site of tumor and that targeting these differences may be a potentially effective approach to preventing or treating cancer metastasis. To explore this innovative and novel approach to the study of cancer metastasis, I will use pancreatic cancer as a model. Pancreatic cancer is known to be a metastatic disease with extremely high mortality rate of up to 98 percent. The primary lesion is in the pancreas, but patients may develop metastasis to the liver, lungs, brain, etc. Pancreatic cancer is the fourth highest cause of deaths due to cancers here in the United States. I will focus on isolating, culturing and performing detailed molecular and functional characterization of cancer cells from blood of pancreatic cancer patients because distant metastases is believed to occur almost entirely via hematogenous spread. The effects of molecularly targeted therapies on the CCCs will then be directly examined to determine the most appropriate personalized cancer management for each patient with pancreatic cancer.”
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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