EGFRvIII in Pancreatic Cancer

Summary

Principal Investigator: Maneesh Jain
Abstract: DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer related death in the United States. There is an urgent need to identify novel biomarkers for early diagnosis and targets for therapeutic interventions. Overexpression of EGFR in PC cells plays a crucial role in the uncontrolled proliferation of neoplastic cells. Amplification or overexpression of the wild-type EGFR (EGFRwt) gene is frequently associated with rearrangements or alternate splicing resulting in the expression of structurally altered EGFR mRNA and protein. EGFRvIII is the most is the most common naturally occurring mutant form of EGFR and is expressed in many cancer types including glioblastoma, breast, ovarian, head and neck, lung and prostate cancer. Although amplification of EGFR and its ligands is well documented in pancreatic cancer, no efforts have been made to study the incidence or involvement of EGFRvIII in pancreatic cancer. Our preliminary results suggest that EGFRvIII is highly expressed in pancreatic cancer tissues. Based on the preliminary findings we hypothesize that "naturally occurring epidermal growth factor receptor variant III (EGFRvIII) contributes to the pathogenesis of pancreatic adenocarcinomas". To test the hypothesis following specific aims are proposed: SPECIFIC AIM I will investigate the expression of EGFR and EGFR variants in human pancreatic tumors by reverse transcriptase- polymerase chain reaction (RT-PCR) and immunohistochemical analysis. PCR- amplification will demonstrate the expression of mRNA. Immunohistochemical analysis using a EGFRvIII specific monoclonal antibody will indicate the presence and cellular localization of the EGFRvIII protein. This aim will provide the information on the incidence of expression of EGFRvIII in human pancreatic tumors. SPECIFIC AIM II will express EGFRvIII in highly tumorigenic (HPAF) and poorly tumorigenic (MiaPaCa) human pancreatic cancer cell lines and immortalized human pancreatic ductal cells (HTERT/HPNE) to establish its contribution to the malignant phenotype. This aim will support our prediction that expression of EGFRvIII in cultured immortal pancreatic cells is sufficient to lead to a transformed phenotype;that the cells will gain the ability to form foci in soft agar and to form tumors in nude mice. Taken together, these studies will provide the incidence and function of a novel naturally occurring variant of EGFRvIII in the lethal pancreatic cancer. The long-term goal of this project is to use the newly developed anti-EGFRvIII antibodies for targeted therapy of pancreatic cancer. PUBLIC HEALTH RELEVANCE: Mutant epidermal growth factor receptor, EGFRvIII is an attractive target for targeted therapy due to its tumor-restricted expression and presence of unique antigenic epitopes. In this grant application, we propose to investigate EGFRvIII's expression in pancreatic tumors (various grades of malignancy), its oncogenic function in immortal pancreatic cells, and its effect on tumorigenecity of pancreatic cancer cells.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer
    Subhankar Chakraborty
    Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198 5870, USA
    Biochim Biophys Acta 1826:129-69. 2012
  2. pmc Early diagnosis of pancreatic cancer: challenges and new developments
    Sukhwinder Kaur
    Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
    Biomark Med 6:597-612. 2012
  3. pmc Emerging trends for radioimmunotherapy in solid tumors
    Maneesh Jain
    1 Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
    Cancer Biother Radiopharm 28:639-50. 2013
  4. pmc Guggulsterone decreases proliferation and metastatic behavior of pancreatic cancer cells by modulating JAK/STAT and Src/FAK signaling
    Muzafar A Macha
    Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198 5870, USA
    Cancer Lett 341:166-77. 2013
  5. pmc Antibody labeling with radioiodine and radiometals
    Suprit Gupta
    Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
    Methods Mol Biol 1141:147-57. 2014
  6. pmc Mucins in the pathogenesis of breast cancer: implications in diagnosis, prognosis and therapy
    Partha Mukhopadhyay
    Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
    Biochim Biophys Acta 1815:224-40. 2011
  7. pmc Monoclonal antibodies recognizing the non-tandem repeat regions of the human mucin MUC4 in pancreatic cancer
    Maneesh Jain
    Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
    PLoS ONE 6:e23344. 2011
  8. pmc Recent trends in antibody-based oncologic imaging
    Sukhwinder Kaur
    Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
    Cancer Lett 315:97-111. 2012
  9. pmc Targeting the EGFR signaling pathway in cancer therapy
    Parthasarathy Seshacharyulu
    University of Nebraska Medical Center, Department of Biochemistry and Molecular Biology, Omaha, NE 68198 5870, USA
    Expert Opin Ther Targets 16:15-31. 2012

Scientific Experts

  • Maneesh Jain
  • Surinder K Batra
  • Sukhwinder Kaur
  • Suprit Gupta
  • Moorthy P Ponnusamy
  • Subhankar Chakraborty
  • Muzafar A Macha
  • Parthasarathy Seshacharyulu
  • Partha Mukhopadhyay
  • Surinder Batra
  • Satyanarayana Rachagani
  • Priya Pai
  • Aaron R Sasson
  • Apar K Ganti
  • Pradeep K Garg
  • Michael J Baine
  • Ganesh Venktaraman
  • Shantibhusan Senapati
  • Sushovan Guha
  • Dhanya Haridas
  • Imayavaramban Lakshmanan
  • Grish C Varshney
  • Sushil Kumar
  • Nicolas Moniaux
  • Ganesh Venkatraman

Detail Information

Publications9

  1. pmc The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer
    Subhankar Chakraborty
    Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198 5870, USA
    Biochim Biophys Acta 1826:129-69. 2012
    ....
  2. pmc Early diagnosis of pancreatic cancer: challenges and new developments
    Sukhwinder Kaur
    Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
    Biomark Med 6:597-612. 2012
    ....
  3. pmc Emerging trends for radioimmunotherapy in solid tumors
    Maneesh Jain
    1 Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
    Cancer Biother Radiopharm 28:639-50. 2013
    ..Further, some of promising approaches to improve tumor targeting, which showed promise in the past, but have now been ignored are also discussed...
  4. pmc Guggulsterone decreases proliferation and metastatic behavior of pancreatic cancer cells by modulating JAK/STAT and Src/FAK signaling
    Muzafar A Macha
    Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198 5870, USA
    Cancer Lett 341:166-77. 2013
    ..In conclusion, our results support the utility of GS as a potential therapeutic agent for lethal PC. ..
  5. pmc Antibody labeling with radioiodine and radiometals
    Suprit Gupta
    Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
    Methods Mol Biol 1141:147-57. 2014
    ..In this chapter, we describe the commonly used methods for radiolabeling and characterizing the antibodies most commonly used radiohalogens (125I/131I) and radiometals (177Lu/99mTc)...
  6. pmc Mucins in the pathogenesis of breast cancer: implications in diagnosis, prognosis and therapy
    Partha Mukhopadhyay
    Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
    Biochim Biophys Acta 1815:224-40. 2011
    ..The potential of mucins as diagnostic and prognostic markers and as therapeutic targets in breast cancer have also been discussed...
  7. pmc Monoclonal antibodies recognizing the non-tandem repeat regions of the human mucin MUC4 in pancreatic cancer
    Maneesh Jain
    Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
    PLoS ONE 6:e23344. 2011
    ..The new domain-specific anti-MUC4 antibodies will serve as important reagents to study the structure-function relationship of MUC4 domains and for the development of MUC4-based diagnostics and therapeutics...
  8. pmc Recent trends in antibody-based oncologic imaging
    Sukhwinder Kaur
    Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
    Cancer Lett 315:97-111. 2012
    ....
  9. pmc Targeting the EGFR signaling pathway in cancer therapy
    Parthasarathy Seshacharyulu
    University of Nebraska Medical Center, Department of Biochemistry and Molecular Biology, Omaha, NE 68198 5870, USA
    Expert Opin Ther Targets 16:15-31. 2012
    ..Several anti-EGFR therapies such as monoclonal antibodies and tyrosine kinase inhibitors have been developed, which has enabled clinicians to identify and treat specific patient cohorts...