Basic scientists focus on understanding how things work, so most don't get the chance to directly impact other people's lives. That's why Michelle Ozbun, PhD, is very excited about her recent grant to study human papillomavirus.
Dr. Ozbun recently won a $275,000 two-year grant from the National Institute of Dental and Craniofacial Research. She is a Professor in the Department of Molecular Genetics and Microbiology and a Professor in the Department of Obstetrics and Gynecology at the University of New Mexico School of Medicine. She is also the Maralyn S. Budke Endowed Professor in Viral Oncology at the UNM Cancer Center. Her work could lead to reducing the chemotherapy and radiation treatments that head and neck cancer patients now endure. And that could improve their quality of life afterward.
Certain strains of HPV cause cancer by forcing the cell to keep copying itself and preventing the cell from using its own natural self-destruct process. "HPV, like all viruses, is an obligate intracellular pathogen," says Dr. Ozbun. "HPV relies on all of the machinery already in the cell in order to reproduce itself." The parasitic virus gives the cell instructions to keep making proteins, to keep multiplying, and to stay alive. Dr. Ozbun is an expert on the chain of cellular events—called a pathway—that HPV uses to infect and hijack the cell. Dr. Ozbun's lab has shown that HPV uses a pathway that starts with a certain kind of cell receptor. The receptor, called EGFR for "epidermal growth factor receptor," is on the surface of the cells HPV infects in the human body. But it was a chance conversation with a clinician at the UNM Cancer Center that linked HPV infection with cancer treatment.
The clinician was Julie Bauman, MD, MPH, now at the University of Pittsburgh. She told Dr. Ozbun that people who had HPV-induced head and neck cancers responded much better to a drug called Cetuximab combined with radiation and chemotherapy. Although all head and neck cancer patients have many side effects like difficulty in talking and swallowing, those whose head and neck cancers were not HPV-induced had a lower response to treatment. Dr. Bauman's observation combined with Dr. Ozbun's knowledge led the two to pursue this link further.
Cetuximab is an FDA approved drug that blocks EGFR. Because EGFR is on the surface of many cells in the human body, Cetuximab has several side effects. Cetuximab affects certain cancer cells more than normal cells because those cancer cells often have a greater number of EGFRs.
Epidermal growth factor binding to the EGFR triggers several pathways in the cell. These pathways encourage the cell to grow. Other proteins, called tumor suppressor proteins P53 and RB, keep these pathways in check in a normal cell. But in cancer cells, which also have many more DNA mutations, P53 and RB are usually absent, malformed or overwhelmed.
Dr. Ozbun knew from her own and others' research that HPV triggers these same growth pathways by forcing the cell to produce viral proteins called E6 and E7. The E6 and E7 proteins make the EGFR more active and degrade the tumor suppressor proteins P53 and RB. Without P53 and RB, the cell stays alive and keeps multiplying. The more active EGFR keeps the cell growing faster than normal. The result is a self-reinforcing loop that snowballs out of control into cancer.
Dr. Ozbun's NIDCR grant will help her learn if Cetuximab can derail this loop. Her research will determine if by blocking EGFR, Cetuximab reduces the amount of E6 and E7 and increases the amounts of P53 and RB in a cell. And because HPV infected cancer cells have fewer DNA mutations, her research will also reveal whether allowing the cell to produce P53 and RB will make the cancer cells more sensitive to chemotherapy drugs and to radiation. If it does, people with HPV head and neck cancers might require less chemotherapy and radiation, have fewer side effects and greater quality of life.
Using other grants, Dr. Ozbun, Dr. Bauman, and Andrew Cowan, MD, PhD at the UNM Cancer Center are planning additional studies in people. Preliminary studies in mice using Cetuximab to sensitize tumors have been successful. And because Cetuximab is already FDA approved, the research team won't need to go through the entire clinical trials process to use it in people. The drug's uses, dosing and side effects are already established. Their studies will show that physicians can use it differently.
"This is super exciting to me," says Dr. Ozbun enthusiastically, "because I'm really seeing the translational aspect. This can really help people." But, she adds, "If we didn't have the background to know what the viral proteins were doing in cell culture or how the cellular proteins are able to help activate the virus, we wouldn't be able to do this. It's really important to understand the basic functions of the cell and the basic functions of viruses in the cell. That can't be overemphasized."
University of New Mexico School of Medicine