Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth most frequent cause of cancer related deaths in United States due to propensity to metastasis, invasion and resistance to chemotherapy. All stage 5-year survival rate is <5% with over 95% of the patients having recurrence of the tumor either locally or in the form of metastasis to other organs. Tumor relapse has been largely attributed to the presence of tumor initiating cells (TIC) or cancer stem cells (CSC). CSCs or TICs are quiescent cells within a tumor that are resistant to chemotherapy and are responsible for tumor recurrence. Thus therapies directed against TICs should lead to decreased tumor recurrence and metastases. Unfortunately, currently no chemotherapeutic agents are known to target TICs. CD133 is one of the surface markers that have been used in isolation and characterization of pancreatic tumor initiating cells. However, the biological role of CD133 is not known. Our group has recently evaluated Minnelide , a water soluble pro-drug of triptolide in pre-clinical studies on multiple animal models of pancreatic cancer with very promising results. However, the effect of Minnelide on prevention of tumor recurrence has not been studied in great detail. The current proposal is focused on elucidating the downstream events that are triggered by CD133 expression on a tumor initiating cell resulting in tumor recurrence and invasion leading to metastasis in this disease and evaluating the effect of Minnelide on this cell population.

Public Health Relevance

Pancreatic cancer is associated with poor prognosis and resistance to current therapeutic regimens. One of the reasons contributing to the grim survival is the rate of tumor recurrence. Tumor initiating cells represented by surface markers like CD133+ cells are responsible for evading standard chemotherapy and cause the relapse of a tumor. However, the downstream mechanisms stemming from expression of these markers to development of a tumor is not known. In the current grant proposal, we aim to investigate the mechanism of tumor initiation as a result of CD133+ and evaluate the biological significance of this molecule in context of tumor development. We would further evaluate the efficacy of Minnelide, a water-soluble variant of triptolide, which will be entering Phase I clinical trials shortly, on these cells. Successful completion of these mechanistic and translational studies will eventually help in planning strategies for the treatment of pancreatic cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Jhappan, Chamelli
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University of Minnesota Twin Cities
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Nomura, Alice; Dauer, Patricia; Gupta, Vineet et al. (2016) Microenvironment mediated alterations to metabolic pathways confer increased chemo-resistance in CD133+ tumor initiating cells. Oncotarget :
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Nomura, Alice; McGinn, Olivia; Dudeja, Vikas et al. (2015) Minnelide effectively eliminates CD133(+) side population in pancreatic cancer. Mol Cancer 14:200