Determining and targeting mechanisms controlling cancer cell division

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OVERALL SUMMARY The Cyclin D-Cdk4/6-Rb-E2F pathway integrates external and internal signals to control cell cycle progression at the G1/S transition of the cell cycle. Alterations in the Cyclin D-Cdk4/6-Rb-E2F pathway are found in the vast majority of human cancers. These alterations are thought to increase the proliferative potential of cancer cells. For example, the functional inactivation of the retinoblastoma (RB1) tumor suppressor or the amplification of Cyclin D genes is a recurrent event in the development of a wide range of human cancers. In the simple consensus model, the retinoblastoma protein Rb inhibits cell proliferation at the G1/S transition of the cell cycle by binding and inhibiting E2F transcription factors. In response to cell growth and proliferative signals, Rb is phosphorylated and inactivated in normal cells by a series of Cyclin-dependent kinase complexes (first Cyclin D-Cdk4/6 and then Cyclin E/A-Cdk2). Phosphorylation of Rb results in the dissociation of Rb from E2F transcription factors thereby causing transcription of genes important for DNA synthesis and other key aspects of cell cycle progression. Thus, cancer cells with constitutively inactive Rb are thought to acquire an increased proliferative potential. Knowledge of the Cyclin D-Cdk4/6-Rb-E2F pathway in normal and cancer cells has led to the development of specific Cdk4/6 inhibitors that have been approved for the treatment of breast cancer and are in clinical trials for several other cancer types. In this paradigm, inhibition of Cdk4/6 results in decreased Rb phosphorylation, which activates Rb’s cell cycle inhibitory function. However, many tumors do not respond to these inhibitors or do so only transiently. Recent observations in patients and pre-clinical models indicate that our understanding of the Rb pathway is not as complete as we previously thought. This may explain the variable results of Cdk4/6 inhibitors in the clinic. The overall goal of this proposal is to gain a deeper structural, molecular, and cellular understanding of the Rb pathway with the ultimate goal to help design new and improved therapeutic strategies targeting this pathway in a broad range of cancer patients. Our first goal is to determine the core mechanisms regulating the Cyclin D-Cdk4/6-Rb-E2F pathway, including how Cyclin D-Cdk4/6 phosphorylates Rb and how previously unknown post-translational modifications regulate Rb and E2F activities. Our second goal is to identify and investigate new functions of Rb pathway components, including new targets of Cyclin D- Cdk4/6 kinases, new functions for Rb and its family members p107 and p130, and new regulatory mechanisms controlling the concentration and activity of E2F transcription factors. Our third goal is to initiate the development of strategies that target the Rb pathway in innovative ways, including molecules that inhibit Cyclin D-Rb association, stimulate the tumor suppressor activity of p107 and p130, and manipulate E2F stability. These goals will be achieved in three inter-related Projects via a comprehensive, synergistic and multi-disciplinary approach. Ultimately, the information gained from these studies may provide new ways to target the Cyclin D-Cdk4/6-Rb- E2F pathway to improve cancer therapy.