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    Awarded Grants
    A Novel Combination Approach of Anti-Her2/Neu and Anti-Prolactin for Breast Cancer

    Scientific Abstract:
    Background: Human breast cancer is the predominant malignancy and one of the leading causes of cancer death in women from the Western society. Over-expression of HER2 protein occurs in 30% of human breast cancers. Women whose tumors over-express HER2 have a poor prognosis with a median survival of 3 years, compared with 6–7 years for HER2-negative cases. Herceptin, a humanized monoclonal antibody directed at the HER2 extracellular domain, has been shown to be effective in HER2 over-expressing breast cancer patients. However, based upon recent clinical trial data, the overall response rate of Herceptin as a single agent is between 20-30% among HER2 positive patients. We hypothesize that one of the reasons that Herceptin is not effective in a majority of patients is due to the fact that over-expressed HER2 proteins are constitutively phosphorylated (activated) in the absence of its cognate ligand. One factor causing constitutive HER2 phosphorylation is locally produced prolactin (PRL) that cross-activates HER2 through PRL receptor acting as an autocrine/paracrine growth factor. Therefore, in order to effectively block HER2 pathway in breast cancer cells, a combination of Herceptin (blocking the extracellular portion of the protein) and inhibition of hPRL-induced cross phosphorylation of HER2 should be considered. In our recent studies, we have demonstrated that G129R, a hPRL receptor antagonist, is able to bind to PRL receptors and completely block PRL induced signal transduction. We have further demonstrated that G129R has anti-breast cancer effects both in vitro and in vivo. More importantly, we have demonstrated in our preliminary studies that there is an additive/synergistic effect between G129R and Herceptin in inhibition of breast cancer cell proliferation. In addition, we have found that this synergistic effect between G129R and Herceptin is, at least in part, through the inhibition of MAPK. Hypothesis and Objective: We hypothesize that over-expressed HER2 in breast cancer cells is constitutively phosphorylated by locally produced PRL. In order to improve the efficacy of anti-HER2 therapy, it is important to block PRL activities. The objective of this study is to test the potential additive/synergistic effects between a PRL antagonist, G129R, and Herceptin in HER2 positive human breast cancer. Specific Aims and Study Designs: There are three specific aims of this proposal. Aim 1, to confirm the additive/synergistic effects between G129R and Herceptin in inhibition of cell proliferation and to establish optimal dose combination of these two drugs using multiple human breast cancer cell lines. Aim 2, to validate the cross-talk mechanism between hPRL/G129R and HER2 in multiple breast cancer cell lines. Aim 3, to confirm the potential additive/synergistic anti-tumor effects of G129R and Herceptin using human breast cancer xenograft nude mouse models. Potential Outcomes and Benefits of the Research: We hope that this two-year pilot study will lay a foundation for designing a more effective therapy for HER2 positive breast cancer and the results of this project will soon be translated into clinical study.

    Lay Abstract:
    Background: Human breast cancer affects one in every eight women in the United States. It has become a leading cause of death in women. Women whose tumors over-express an oncogene product, HER2, have a poor prognosis with a median survival of 3 years, compared with 6–7 years for HER2-negative cases. Current therapy using a monoclonal antibody, Herceptin, to block HER2 protein at the cell surface has proven to be effective. However, the overall clinical response rate to Herceptin treatment is less than 30%, which is far from satisfactory. We believe that the unsatisfactory response to Herceptin treatment is due to the fact that majority of over-expressed HER2 in cancer cells has already been activated by human prolactin (hPRL), a female hormone intimately related to breast cancer development, through an intracellular cross-talk mechanism. The activated HER2 protein fires proliferation signals without the need for additional stimulation. Herceptin by nature is designed only to block HER2 at the cell surface to prevent it being activated. Hence, if HER2 is activated by hPRL/PRL receptor via intracellular interaction, Herceptin will not be effective in stopping the cancer cell proliferation. Therefore, in order to effectively block HER2 signaling, anti-PRL measure should be considered. In our recent studies, we have successfully developed a hPRL blocker, G129R. We have demonstrated that G129R is able to shut down hPRL initiated intracellular signaling activities and is effective as a single agent in inhibition of breast cancer cell proliferation both in cell culture and in mice. More importantly, we have demonstrated in our preliminary study that there is indeed an additive effect between Herceptin and G129R in inhibition of breast cancer cell proliferation. Objective and Hypothesis: In this proposal we attempt to test the idea of using Heceptin together with G129R as of a combination therapy targeting HER2 positive breast cancer. We hypothesized that since Herceptin blocks HER2 at the cell surface and G129R stops HER2 from being activated by hPRL, this approach should provide a “one-two punch” to HER2 signaling therefore effectively block proliferation of HER2 positive breast cancer. Specific Aims and Study Designs: Aim 1, to confirm the additive/synergistic effects between Herceptin and G129R in inhibition of cell proliferation using multiple human breast cancer cell lines; (2) to confirm the molecular mechanism between Herceptin and G129R by evaluation of the status of HER2 and another signaling molecule (MAPK) after the combination treatment; and (3) as an ultimate test, we will evaluate the growth pattern of breast tumor in nude mice bearing human breast cancer after combination treatments. Potential Outcomes and Benefits of the Research: We hope the results from this project will be translated into clinical trials in the near future. We hope that this novel combination therapy can be used to improve the outcome of those patients with the most aggressive types of breast cancer.