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    Research Grants Awarded

    Rational Design of Combinational Targeted Therapeutics in Breast Cancer: Towards Improving Patient Outcomes

    Study Section:
    Treatment

    Scientific Abstract:
    Background: Therapies targeting molecular pathways underlying carcinogenesis offer a novel attractive treatment strategy but it is critical to define targets that drive tumorigenesis. We will utilize abnormal signaling signatures in breast cancer cell lines which reflect genetic aberrations in patient tumors as models to match, classify, and predict the sensitivity of human tumors to targeted therapies. Synthetic lethality analysis will identify important signaling nodes and rational therapy combinations. Objective/Hypothesis: Functional reverse phase lysate arrays (RPPAs) can globally define protein signaling networks in human tumors and identify cell lines with representative genomic abnormalities. These data will be integrated into a “fingerprint” database and allow rapid assessment of the 'on and off target' activity of novel therapeutics, their effects on functional outcomes, and identification of therapy combinations effective in particular patients. Specific Aims: 1. To determine the effects of specific genomic alterations on cell signaling networks in breast cancer cell lines and human tumors. 2. To identify optimal combinations of targets by exploring synthetic lethal interactions between chemotherapy, signaling inhibitors, and RNA interference in cell lines. Study Design: We have analyzed DNA copy number, transcriptional profiles, and protein signaling in 100 breast tumors and 55 cell lines. We will perform RPPAs in cell lines treated with specific growth factors and inhibitors. We will match protein signaling patterns to patient tumors with defined genomic and pathologic characteristics. This will allow the concordant interrogation of multiple intra-cellular signaling molecules at the functional level (e.g. phosphorylation) to be integrated into a “fingerprint” database to identify novel therapeutic targets. We will identify and validate synthetic lethal interactions using genetic manipulation, conventional therapies, and targeted inhibitors. By comparing to effects on viability and cell cycle progression, we will define optimal therapeutic strategies in different breast cancers. Strong bioinformatics assistance will strengthen assay design and data interpretation. Potential outcomes and benefits: This study provides a novel approach to explore breast cancer functional proteomics and genomics, thus leading to better understanding of cancer pathobiology and to the discovery of novel relevant therapeutic targets for clinical evaluation.

    Lay Abstract:
    Background: Targeted therapeutics counteract tumor molecular aberrations, offering an attractive new approach with higher efficacy and less toxicity than conventional chemotherapy. For maximal efficiency, it is vital to target aberrations that drive tumor behavior. Using novel technologies, we believe that we can identify breast cancer cell lines that reflect particular subgroups of patients. These cell lines will be utilized to identify and validate new therapeutic strategies to improve patient outcomes. Objective/Hypothesis: Identification of important molecular aberrations in breast cancer cell lines provides “fingerprints” matching human tumors. Cell lines will function as models to study novel therapeutic strategies and to predict in vivo responsiveness to particular therapies in different patients. We propose a high content screening assay, tissue lysate arrays, to rapidly detect cellular protein activities and identify concordant abnormalities in cell lines and breast tumors. Specific aims: 1. To determine effects of specific genomic alterations on cell signaling networks in breast cancer cell lines and human tumors. 2. To identify optimal combinations of targets for breast cancer therapy by exploring synthetic lethal interactions between chemotherapy drugs, signal transduction inhibitors, and RNA interference in breast cancer cell lines. Study design: We will analyze alterations in protein expression/activity and their effects on cell signaling pathways and networks in breast cancer cell lines and human tumors. These functional alterations will be integrated into a “fingerprint” database to assess the consequences of genomic aberrations on patient outcomes. Major alterations will be defined as potential targets. We will determine in vitro sensitivity to therapy directed against these targets, and in combination with chemotherapy and existing small molecule inhibitors targeting major signaling pathways in breast cancer cell lines with particular genetic aberrations reflective of human tumors. Potential ourcomes and benefits: This study provides a novel approach to link genomic and functional proteomic alterations. It offers the opportunity to fully understand cancer pathobiology and to promote drug discovery and development for clinical evaluation. We will learn to treat cancer patients individually based on particular molecular changes leading to more effective and less toxic therapy.