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A TGF-beta Responsive Gene Therapy Vector (TRGT) that Specifically Kills Metastatic Breast Cancer
Background: Lymph node status is used in the diagnosis of breast cancer, with node-negative breast cancer (NNBC) patients receiving the best prognosis. However, 25-30% of NNBC patients will have recurrence within 5 years. Due to the potential side effects (i.e. sickness or additional cancers) prophylactic therapy is not always administered. Thus, there is a need for therapies that specifically target a cancer cell within a non-cancerous background. This research describes the development of a novel gene therapy vector (TRGT) that will exclusively kill cells that are both positive for c-myc amplification AND resistant to Transforming Growth Factor-beta (TGFbeta) mediated growth arrest, two distinguishing characteristics of breast cancer. In up to 45% of breast cancers, amplification of the transcription factor c-myc is detected, and this is associated with decreased survival rates. TGFbeta arrests the growth of epithelial cells, but most breast cancer cells are resistant to its action. The TRGT vector contains two TGFbeta dependent promoters. Promoter SBE will allow TGFbeta dependent expression of an apoptosis protein and promoter INR allows expression of an inhibitor of this apoptosis protein. The TRGT vector, with its second promoter, is innovative and safer because it takes advantage of a normal link between c-myc and the TGFbeta pathway. In a wt cell in the presence of TGFbeta the TRGT vector will express both the apoptosis gene (SBE ON) and the apoptosis inhibitor (INR ON) simultaneously, blocking apoptosis of the normal cell. In a breast cancer cell, however, where c-myc levels are high even in the presence of TGFbeta, the apoptosis inhibitor will NOT be expressed (INR OFF), while the apoptosis gene is expressed (SBE ON), selectively killing the cancer cell. This project will validate the TRGT vector concept. Specifically, we will construct and test the TRGT vector in human breast cancer cell lines, to determine a promoter/apoptosis/inhibitor combination that selectively and effectively kills breast cancer cells while not affecting normal epithelial cells. This is a proof in principle study to ascertain whether the TRGT vector is worthy of future development. The vector is innovative because it takes advantage of a cellular condition peculiar to breast cancer cells, so the associated toxicity should be low. It capitalizes on knowledge about the TGFbeta pathway and translates this expertise into a potential therapeutic for breast cancer.
Breast cancer is the most common from of cancer in women from developed countries, with approximately 200,000 new cases diagnosed per year in the U.S. Prognostic factors such as tumor size, hormone receptor status, age, histology, ploidy and proliferation index are used to define subgroups of high-risk patients. Currently, lymph node status is also used in the diagnosis of breast cancer, with node-negative breast cancer patients (NNBC) receiving the best prognosis. In NNBC cases, it is hoped that the cancerous cells have not spread from the initial tumor site into the rest of the body, resulting in cancer-free lymph nodes. However, 25-30% of NNBC patients will have recurrence within 5 years, suggesting that the NNBC designation is too broad. Most chemotherapies do not differentiate between cancer cells and non-cancer cells, and thus have severe toxic side effects. Because of this additional therapy is not usually administered to NNBC patients. Thus, there is a need for therapies that specifically target a cancer cell within a non-cancerous background. This research will test the concept that a gene therapy vector (TRGT) can be developed that will specifically kill breast cancer cells that are both positive for c-myc amplification AND resistant to Transforming Growth Factor-beta (TGFbeta) mediated growth arrest, two hallmarks of breast cancer. TGFbeta arrests the growth of normal breast cells, but most breast cancer cells are resistant to this response. c-myc is a promoter of cell growth, and in up to 45% of breast cancers, amplification of c-myc is detected. Therefore, a breast cancer cell that is resistant to TGFbeta (or a signal to stop growing) and has amplified c-myc (or a hyperactive signal to grow) is in a perpetual “go” state, and may actually signify a very aggressive type of cancer. Thus, targeting this breast cancer cell may actually target a more metastasis prone phenotype that is highly desirable to eliminate. The TRGT vector expresses a protein that causes cell death, as well as a potent inhibitor of that death-inducing protein. In a normal cell, the death protein and its inhibitor are expressed simultaneously so the cell lives. In a cancer cell, however, only the death-inducing protein is expressed, so that cell dies. We will test the TRGT vector in human breast cancer cells. TRGT is innovative because it takes advantage of a condition peculiar to breast cancer (myc expression/ TGFbeta resistance), so the associated toxicity will be low. This type of prophylactic therapy is desperately needed.