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    Research Grants Awarded

    Using Genomics And Proteomics To Develop Effective Therapies For Er-Negative Breast Cancer

    Grant Mechanism:
    Promise Grant

    Scientific Abstract:
    Developing Effective Therapies for ER-negative Breast Cancer using Genomics and Proteomics It is evident that aberrant activation of signal transduction pathways plays a crucial role in breast cancer development and progression. For estrogen receptor (ER)-positive breast cancers, ER has been shown to be a critical growth regulatory molecule. Indeed, targeting ER using hormonal agents such as anti-estrogens or aromatase inhibitors is an effective treatment strategy for ER-positive breast cancers. Similarly, for ErbB2 (HER2/neu) over-expressing breast cancers, targeted therapy directed at this protein is an effective treatment for ErbB2-positive breast cancers. Unfortunately, many breast cancers do not express ER or ErbB2, and no targeted therapy is available for these particularly aggressive cancers. The long-term goals of these studies are to identify the critical growth regulatory pathways in ER-negative breast cancers and to develop effective targeted therapy to treat these aggressive breast cancers. To achieve this goal we have formed a multidisciplinary team of basic and clinical breast cancer researchers from Baylor College of Medicine and MD Anderson Cancer Center who are using genome-wide approaches for target identification. We are using genomic, transcriptomic, and proteomic approaches to identify the signaling molecules that are aberrantly expressed in ER-negative breast cancer, and that are critical growth regulators of ER-negative breast cancers. We hypothesize that: (1) high-throughput profiling of human ER-negative breast cancers at the DNA, RNA, and protein levels will identify molecules aberrantly expressed in these cancers, (2) that specific targeting of these aberrantly expressed molecules will eliminate breast cancer in preclinical models, and (3) that drugs that inhibit these critical signaling pathways will effectively treat ER-negative breast cancer in women with this disease. This genome-wide translational program will enable us to develop and test specific signal transduction inhibitors for the treatment of ER-negative breast cancer. To accomplish this we will conduct three inter-related projects. In Project 1 we will identify novel targets for the treatment of ER-negative breast cancer using high-density genomic, expression, and proteomic arrays. In Project 2 we will determine whether inhibition of these novel targets in ER-negative breast cancers suppresses the growth or induces death of these cancer cells. In Project 3 we will conduct novel clinical trials to target pathways discovered in genomic and proteomic analysis of ER-negative breast cancers. An essential component of this research program is the interaction between the participating basic and clinical investigators, bioinformatics experts, breast cancer survivors, and pharmaceutical houses that can provide novel signaling inhibitors for clinical testing. This collaborative project will greatly accelerate the development and testing of targeted therapies for effective treatment of ER-negative breast cancer and is expected to significantly reduce mortality from this aggressive form of breast cancer within 10 years.

    Lay Abstract:
    Developing Effective Therapies for ER-negative Breast Cancer using Genomics and Proteomics Estrogen receptor (ER)-negative breast cancers are particular aggressive breast cancers that are currently treated with chemotherapy. On the other hand, ER-positive or progesterone receptor (PR)-positive breast cancers are typically treated with anti-estrogen drugs such as tamoxifen, fulvestrant, or aromatase inhibitors. These drugs have significantly improved the survival of women with ER-positive or PR-positive breast cancer. However, these anti-estrogen drugs are of no benefit to women with ER-negative breast cancer. These women instead are treated with chemotherapy and must endure the significant toxicity of such therapy. Therefore, there is an urgent need to develop effective, non-toxic, molecularly targeted therapies for the treatment of women with ER-negative breast cancers. It is possible to target the abnormal signal transduction pathways found in breast cancer. Herceptin (or trastuzumab) is a targeted therapy against the growth factor receptor, ErbB2 (HER2/neu), which has been shown to be effective in treating some but not all ErbB2-positive breast cancers. Unfortunately, many breast cancers do not express ER, PR, or ErbB2 (defined as triple-negative breast cancer), and no effective therapy is available for these particularly aggressive ER-negative breast cancers. Our long-term goals of these studies are to discover the critical pathways in ER-negative breast cancer that regulate the growth of this cancer, and to develop and test effective targeted therapies to treat women with these aggressive breast cancers. To achieve this goal we have formed a team of basic and clinical breast cancer researchers from Baylor College of Medicine and MD Anderson Cancer Center who are using genome-wide approaches to identify future drug targets. We are using innovative ways at genome and protein levels to find the molecules that are abnormally produced in ER-negative breast cancer. We believe that these molecules are critical for developing ER-negative breast cancers. We hypothesize that: (1) high-throughput screening at the DNA, RNA, and protein levels will identify abnormally produced molecules in ER-negative breast cancers, (2) that blocking the expression of these abnormal molecules will reduce cancer cell growth or induce cancer cell death, and (3) that drugs that inhibit these abnormal molecules or their signaling pathways will effectively treat ER-negative breast cancer. This translational research program will allow us to develop and test molecularly targeted drugs for effective treatment of ER-negative breast cancer. To accomplish this we will conduct three inter-related projects. In Project 1 we will identify novel targets for the treatment of ER-negative breast cancer using new technologies of high-density DNA-, RNA-, and protein-based assays. In Project 2 we will determine whether inhibition of the novel targets in ER-negative breast cancers suppresses the growth or induces death of these cancer cells in preclinical studies in animals. In Project 3 we will conduct novel clinical trials to target the abnormal pathways discovered in DNA, RNA, and protein studies of ER-negative breast cancers. An essential component of this research program is the interaction between the participating basic and clinical investigators, bioinformatics experts, breast cancer survivors, and pharmaceutical houses. This collaborative project will greatly accelerate the development and testing of new drugs for effective treatment of ER-negative breast cancer and is expected to significantly reduce deaths from this aggressive form of breast cancer within 10 years.