Research in the laboratory of Larry M. Karnitz, Ph.D., studies what happens when radiation, chemotherapy or both cause DNA damage that activates specific signaling and repair pathways. Specifically, Dr. Karnitz's lab focuses on determining how these pathways contribute to tumor cell survival. Using this information, Dr. Karnitz then seeks ways to disrupt these pro-survival pathways, translate these discoveries into the clinic to increase the effectiveness of chemotherapy and radiation therapy, and improve the prognoses of patients with cancer, with special focus on acute myeloid leukemia and ovarian cancer.
- The 9-1-1-ATR-Chk1 signaling pathway. Dr. Karnitz's lab discovered and characterized a protein complex that is a pivotal activator of a radiation and chemotherapy-activated checkpoint pathway. This complex, dubbed the 9-1-1 complex because it is composed of the proteins Rad9, Hus1 and Rad1, regulates the activation of ATR and Chk1, two protein kinases that relay the checkpoint signal. Together, the 9-1-1 complex, ATR and Chk1 help tumor cells survive chemotherapy. Ongoing studies are identifying how this pathway promotes survival.
- Inhibiting the 9-1-1-ATR-Chk1 signaling pathway to enhance tumor killing. Dr. Karnitz has also looked for ways to disrupt this pathway as a means to sensitize tumors. In one approach, his lab showed that Hsp90 inhibitors deplete Chk1. Chk1 promotes the survival of tumor cells treated with the chemotherapy agents gemcitabine and cytarabine, two nucleoside analogs that block DNA replication and are highly active treatments for ovarian cancer and leukemia, respectively. This finding was translated into clinical trials that combine these chemotherapy agents with an Hsp90 inhibitor to deplete Chk1. In another approach, Dr. Karnitz's research is partnering with pharmaceutical companies to examine the effects of ATR- and Chk1-inhibiting drugs on tumor cells and move these drugs into clinical trials in leukemia and ovarian cancers.
- Poly ADP-ribose polymerase (PARP) inhibitors sensitize ovarian cancer cells to floxuridine, a drug with activity in ovarian cancer. Dr. Karnitz's lab discovered that PARP enzyme inhibitors, which have just been approved by the Food and Drug Administration (FDA) to treat ovarian cancer, greatly sensitize ovarian cancer cells to floxuridine, an FDA-approved drug that has activity in ovarian cancer. Based on these discoveries, Dr. Karnitz and clinical colleagues have initiated a clinical trial of floxuridine plus the PARP inhibitor veliparib in patients with ovarian cancer at Mayo Clinic.
- CDK12 and ovarian cancer. CDK12 is mutationally inactivated in ovarian cancers, and this leads to decreased levels of DNA repair proteins, including BRCA1. Dr. Karnitz's lab is studying how CDK12 regulates the expression of BRCA1 and other genes, and assessing whether CDK12 levels predict responses to chemotherapies used to treat ovarian cancer, including poly(ADP-ribose) polymerase (PARP) inhibitors.
Significance to patient care
Nearly all cancers are treated with chemotherapy, radiation therapy or a combination of the two. These therapies kill tumors by damaging DNA, blocking DNA replication or both. Although these treatments often shrink tumors, they do not always eradicate the tumors; the tumors may 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. Dr. Karnitz's research is aimed at enhancing the effectiveness of tumor-attacking therapies.