Request for Funding
Medical Student Research Fellowship for Summer 2011

All descriptions must contain enough detail to permit an assessment of the problem that is to be addressed and the methodologies that are to be employed. Please be careful to outline the role that the student will play in the project that is described. Please ensure that all relevant approval numbers (IRB, IACUC) are provided.

Mentor: Drs. E. Vitetta, L. Pop, and I. pop
Department:  Cancer Immunobiology Center
Room number: NB9.116
Mail Code: 8576
Phone Number: 214- 648- 1217
Email: ellen.vitetta@utsouthwestern.edu, laurentiu.pop@utsouthwestern.edu, iliodora.pop@utsouthwestern.edu
Project title: Stem cells in pancreatic cancer cell lines.

Human subjects IRB approved project number (where applicable): NA

Animal subjects IRB approved project number (where applicable): 2009-0375

Project type. Basic Research

Brief Description of Project:

Pancreatic cancer is a uniformly fatal cancer with few treatment options. Over the past three decades, the overall 5-year survival rate for pancreatic cancer patients has remained at 5%, despite the progress in understanding cancer biology and the development of new targeted therapies. One hypothesis to explain the resistance of pancreatic cancer to treatment suggests the involvement of cancer stem cells (CSC). Such cells can generate tumors by their ability to renew and differentiate into several cell types, surviving (despite treatment) long enough to cause recurrence and metastases. To increase the rate of survival of pancreatic cancer patients, early detection and therapeutic targeting of CSCs could be of a critical importance. There are studies which report different cocktails of markers to identify this population. However, conclusions are controversial.

Thus far, we have characterized eight pancreatic cancer cell lines for growth factors, receptors, adhesion molecules, angiogenic factors and molecular markers for treatment resistance. Different classes of chemotherapeutic agents, monoclonal antibodies and small-molecule inhibitors were tested for their activity on these cells. All the cell lines were transplanted in SCID-SCRF-M mice and grow in vivo. Our data show enormous heterogeneity in these cell lines, which may explain resistance to conventional treatments and difficulties in establishing of new therapies. The Aim of this project is to identify and CSC subpopulations with specific phenotypes (i.e. predominantly tumorigenic, invasive, resistant to treatment). The knowledge provided by this study will eventually be applied to fresh and frozen pancreatic cancer samples with a final goal of identifying any molecular targets susceptible to effective anticancer strategies.

Specific Aims:

  1. To grow pancreas cell lines in culture (ongoing).
  2. To analyze CSC- specific cell- surface markers in human pancreatic cancer cell lines (CD24, CD29, CD44, CD97, CD117, CD133, CD166, CD326, and ALDH1 activity); This will be done by flow cytometery.
  3. To study the gene and protein expression profiles of the main markers of CSC tumorigenesis in pancreatic cancer; the following specific markers will be investigated:
    1. Hedgehog signaling pathway: PTCH1, SMO, GLI1, GLI2, SUFU;
    2. Notch signally pathway: NCSTN, NOTCH1, NOTCH2;
    3. Wnt signaling pathway: Wnt1, AXIN 2, GSK-3, APC;
    4. Embryonic stem cell renewal: BMI, OCT4, NANOG, SOX2;
  4. To study the gene and protein expression profiles of the main markers of CSC invasiveness and resistance to therapy in pancreatic cancer; for this approach, we will investigate the following molecules: CXCR4, ABCB1, ABCG2, STAT3, CYP2C8, and TERT. This will be done by flow cytometry, Western Blot, and semi-quantitative RT-PCR.

 

Previous Research Activities or Publications with Medical Students

  1. Rotating Medical students:

2004: Abdula, M., Aguirre, Y., Calexo, S., Guinn, S.,
2005: Parks, S.
2006: Crank, M., Grodin, J.,
2007: Rukayat, R.
2008: Adelagun, R., Bryant, B.
2009: Vo, T.
2010: Aloiso, G.

  1. Publication from medical students:

 

  1. Spiridon, C., Guinn, S., Vitetta, E.S. A comparison of the in vitro and in vivo activities of IgG and F(ab) ‘2 fragments of a mixture of three anti-Her-2 antibodies. Clinical Cancer Research, 10:3542-3551, 2004.
  2. Ghetie, M-A., Crank, M., Kufert, S., Pop, I., Vitetta, E.S. Rituximab but not other anti-CD20 antibodies reverses multidrug resistance in two B lymphoma cell lines, blocks the activity of P-glycoprotein (P- gp), and induces P-gp to translocate out of lipid rafts. J immunoter, 29: 5, 536-544, 2006.