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Novel therapy for pancreatic cancer

Institution: University of California, Irvine
Investigator(s): Hung Fan, Ph.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6RT-0266 Award: $452,332
Subject Area: Cancer
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Pancreatic cancer is a deadly malignancy. The most important overall risk factor in the general population for developing this cancer is tobacco smoking. Many patients are dead within months of diagnosis and less than 1 in 100 people with this disease will be alive 5 years after the diagnosis is established. Complete cures can only be achieved when the diagnosis is made at an early stage and if the patient is referred immediately for surgery. Unfortunately, in the vast majority of patients, the disease has already spread outside the pancreas at the time of diagnosis, and surgery is no longer feasible. These patients may therefore undergo partial surgery for relief of symptoms, or receive radiation treatment and/or chemotherapy. However, none of these treatments prolong survival significantly.

The reasons for the resistance of pancreatic cancer to therapy are not clearly understood, but may relate to the fact that these tumors produce many proteins which enhance the growth of cancer cells. These proteins work together to protect the cancer cell from dying in response to therapy. Work from our laboratory has established that pancreatic cancers produce large quantities of an important growth regulating protein called epidermal growth factor receptor, and that the presence of this receptor contributes to poor patient prognosis and disease progression. We also found that blocking the actions of this protein with a genetically engineered gene can inhibit the growth of pancreatic cancer cells and that this gene can be placed in a virus to infect the cells and reduce their growth. Therefore, in the present proposal we want to design novel viruses that will selectively home in on pancreatic cancer cells and inhibit their growth. This work will also have significant implications for treating other malignancies that are associated with tobacco smoking, such as bladder, lung, breast, and ovarian cancer.

Final Report
The goal of this research project was to develop gene therapy approaches for the treatment of tobacco-related cancers. In particular, we are focusing on pancreatic cancer. Pancreatic cancer is a highly fatal malignancy, and the main causal factor associated with this disease is tobacco smoking. Our approach has been to evaluate a novel class of therapeutic molecules called dominant negative growth factor receptors. Pancreatic cancer cells frequently express abnormal amounts of molecules called growth factor receptors, and we have found that if we induce specially altered forms of these molecules (dominant negative receptors or DNRs) into pancreatic cancer cells, the tumorigenicity of the cells is inhibited. In this project, we are developing improved techniques to introduce the DNRs into pancreatic cancer cells. These techniques involve use of “vectors” based on two kinds of viruses – retroviruses and adenoviruses. We are both testing the efficiency of retroviral vectors and adenoviral vectors expressing DNRs to inhibit pancreatic cancer cell growth in animal model systems, and we are also developing modified vectors that may more specifically target pancreatic cancer cells in comparison to normal pancreatic cells.

During this project, we developed adenoviral vectors expressing DNRs based on two growth factor receptors – EGFR and FGFR-1. We previously had used only retroviral vectors expressing the EGFR DNR. The advantage of adenoviral vectors is that it is possible to generate higher concentrations, so that in the context of therapy it should be easier to introduce the therapeutic molecule in a high percentage of the cancer cells. Infection of pancreatic cancer cells with the adenoviral vectors expressing the EGFRs led to inhibition of growth of these cells. This supports the possibility of using these vectors as therapies in management of pancreatic cancer. We also studied genes that are over-expressed in pancreatic cancer cells. In theory, regulatory sequences from such genes could be used to drive expression of the DNRs in our vectors; thus, the DNRs would be preferentially expressed in pancreatic cancer cells as opposed to normal pancreatic cells. In this project, we focused on the HER-3 gene that is over-expressed in many pancreatic cancers, and we identified the regulatory sequences that govern its over-expression. We found that the HER-3 gene is regulated differently in pancreatic cancer cells as opposed to breast cancer cells, and regions of the gene responsible for the high level expression in pancreatic cancer cells were identified. In the future, HER-3 regulatory sequences may be used to develop second generation retroviral and adenoviral vectors that more specifically express DNR in pancreatic cancer cells. These experiments have moved us closer to the potential application of the DNR molecules as novel therapeutics in treatment of human pancreatic cancer.
Publications

Suppression of FGF receptor signaling inhibits pancreatic cancer cell growth in vitro and in vivo
Periodical: Gastroenterology Index Medicus:
Authors: Wagner M, Lopez ME, Cahn M, Korc M ART
Yr: 1998 Vol: 114 Nbr: Abs: Pg: 798-807