The goal of the DNA Damage Networks project continues to be development of statistical and physico-chemical models that describe the cellular response to DNA damage at the network and systems biology level.
We are developing experimental and computational methods for monitoring the time-dependent activity of a large number of intracellular protein kinases and signaling molecules, and correlated their activity with the cellular phenotypes of DNA damage-induced cell cycle arrest and re-entry, apoptosis or senescence using quantitative mathematical models. We are applying these measurement and modeling methods to understand how genetic alterations in DNA damage signaling networks, and cross-talk between the EGFR signaling network and the DNA damage signaling network, modify the clinical response of human tumors to currently used genotoxic therapies. Experiments focus on human lymphoma and breast cancer cells, building directly upon our experimental and modeling work in lymphoblastoid and human osteosarcoma cells during the prior funding period. The resulting models of DNA damage-induced signaling and phenotypic will be tested at a variety of scales, including in vitro cell culture systems, murine xenografts, and mouse cancer models. The ultimate goal is to apply these models to predict and optimize the responsiveness of human tumors to DNA damaging therapies and therapy combinations, identify patient- and tumor-specific treatments based on the status of their DNA repair and signal transduction networks, and define new targets and drug combinations that enhance the chemotherapeutic response. The DNA Damage Networks program is closely integrated with the other two core programs in our TCNC, the Mitogenic Networks program and the Migration Networks program through both a shared interest in modulation of tumor cell behavior and therapeutic response by the EGFR signaling pathway, and in the effects of DNA damage on tumor cell proliferation and migration.
Specific Aim 1 - Analysis of breast cancer cell responses to chemotherapeutic agents
Specific Aim 2 - Analysis of lymphoma cell responses to chemotherapeutic agents
Specific Aim 3 - Integrating models for DNA damage response, cell cycle, apoptosis, and ErbB signaling