Nearly all cancers are treated with chemo- and/or radiotherapy, which kill tumors by damaging DNA and/or blocking DNA replication. Although these treatments often shrink tumors, they do not always eradicate the tumors; the tumors return and are usually resistant to further therapy. Not surprisingly, tumors are not passive bystanders when they are attacked by therapies. They respond to these assaults by activating signaling and repair pathways that fix the damage and promote tumor cell survival.
As a means to enhance the effectiveness of these therapies, my lab has taken a two-pronged approach. First, we use sophisticated biochemical and cell biology approaches to identify the signaling and repair pathways that are triggered by chemotherapies. Second, we then search for ways to disrupt these pro-survival pathways and translate these discoveries into the clinic to increase the effectiveness of chemo- and radiation therapy and improve the prognosis of patients with cancer.
One specific area of interest focuses on the checkpoint signaling pathways, which are activated when chemotherapy agents cause DNA damage and/or block DNA replication. My lab has played a seminal role in the discovery and deep biochemical characterization of a protein complex that is a pivotal activator of a checkpoint pathway. This complex, which we dubbed the 9-1-1 complex (because it is composed of Rad9, Hus1, and Rad1), promotes the activation of ATR and Chk1, two protein kinases that relay the checkpoint signal to promote survival. Together, the 9-1-1 complex, ATR and Chk1 help tumor cells survive chemotherapy. Accordingly, we then looked for ways to disrupt this pathway as a means to sensitize tumors. These studies led to our finding that Hsp90 inhibitors, which are now in clinical trials, deplete Chk1. Because Chk1 promotes the survival of tumor cells treated with the chemotherapy agents, gemcitabine and cytarabine (two nucleoside analogs that block DNA replication), this finding was translated into ongoing clinical trials that combine an Hsp90 inhibitor to deplete Chk1 with gemcitabine and cytarabine, two highly active treatments for ovarian cancer and leukemia, respectively. Current studies are now focused on identifying additional functions for the 9-1-1 complex, the role(s) of this pathway in tumors treated with other chemotherapy agents, and determining novel way to combine small molecule Chk1 inhibitors, which are now in clinical trials, with additional chemotherapy agents to most effectively treat tumors.