Michelle Ozbun, PhD
News — Like a football team disrupting the opponent’s play, Michelle Ozbun, PhD, and Jason McConville, PhD, at The University of New Mexico Comprehensive Cancer Center are designing a gel to prevent cancers caused by human papillomaviruses (HPVs).
No other antiviral treatments for HPV diseases are available, yet HPVs account for nearly 5% of cancers worldwide. They infect only skin or mucus membranes, and in some cases, an infection may develop into a wart – a non-cancerous skin growth. A few of the 300 HPV varieties cause growths that can develop into cancers of the cervix, throat, anus, genitals and skin.
“They can be very pathogenic,” says Ozbun, a virologist who has dedicated her career to studying HPV infections.
Although vaccines that prevent HPV infections are available, many people remain unprotected. They have already been exposed to the virus, they refuse or cannot afford the vaccine, or they cannot receive the vaccine for medical reasons. In developing countries, many people do not yet have access to the vaccine.
The antiviral gel, Ozbun hopes, may help all of these people. The idea for administering a treatment via a topical gel came from research conducted in Ozbun’s lab to study how HPV infects cells and causes diseases.
Like all viruses, HPVs take over a living cell’s internal machinery to produce more copies of themselves. Those copies then infect more cells. HPVs also reprogram cells to reproduce more frequently, which can lead to a tumor.
Ozbun’s team studied a series of chemical reactions in skin cells called the MEK/ERK pathway. The pathway encourages skin cells to reproduce.
In uninfected skin cells, the MEK/ERK pathway shuts off at a certain time in the cell’s life cycle, allowing the cells to mature and eventually die. Newer cells push the dead cells into the upper layers of skin, where they form the skin’s protective barrier.
In 2021, Ozbun’s team published study results showing that HPV’s cancer-promoting proteins were found only in the deepest layers of skin. In HPV-infected cells in this skin layer, the virus uses the cells’ MEK/ERK pathway to produce proteins called E6 and E7. These proteins induce cells to multiply.
Under most circumstances, the MEK/ERK pathway shuts off in the HPV-infected skin cells. The cells stop making E6 and E7, and the virus then uses the cells to produce the other proteins it needs to make new viral particles.
Ozbun discovered that when the MEK/ERK pathway fails to shut off in HPV-infected skin cells, those cells continue to produce E6 and E7. They keep multiplying and can become precancerous or cancerous.
“The most important proteins are E6 and E7,” Ozbun says, “because they cause the cell to divide. They are always present in HPV infection-generated cancers. They are necessary but not sufficient for cancer development.”
Ozbun’s team studied the E6 and E7 proteins produced through the MEK/ERK pathway in HPV-infected precancerous cells.
“Something happens during cancer progression that prevents those HPV oncogenes from getting turned off,” she says. “And this something pushes the cells to multiply uncontrollably.”
When Ozbun’s team treated HPV-infected skin cells and lab-grown skin with a drug that hinders the MEK/ERK pathway, these cells stopped producing the E6 and E7 proteins and behaved more normally.
“We call it cancer interception,” Ozbun explains, “because we’re keeping the tumor from turning into cancer.”
Ozbun’s team then conducted a proof-of-concept study in live animals with precancerous skin tumors.
For this study, the researchers used drugs that the U.S. Food and Drug Administration (FDA) has already approved for treating some types of melanoma and lung cancers. The drugs, cobimetinib and trametinib, are usually given to people by mouth. Scientists have conducted studies showing that these drugs shut down the MEK/ERK pathway.
The animals were divided into five groups. A control group received just a liquid with no drug. A second group received a low dose of cobimetinib; a third group received a high dose of cobimetinib. The fourth and fifth groups received low and high doses of trametinib.
The animals’ tumors responded to the drugs. The tumors on the animals treated with cobimetinib did not grow, but they did not shrink, either. However, the tumors on the animals treated with both doses of trametinib started shrinking eight days after the start of treatment and were much smaller after 30 days.
But the oral form of this drug is very toxic to both animals and people, Ozbun says.
The team needed another way to get the drug to HPV-infected skin cells, so they created a gel that is absorbed through the skin and shuts down the MEK/ERK pathway. They hope this approach will not only kill the precancerous cells but also hamper further HPV infection.
The use of trametinib as a gel is new. So, although the drug has FDA approval for treatment of melanoma, pre-clinical trials are needed to study the gel’s side effects and effectiveness in people.
Ozbun’s team is conducting their first pre-clinical study in live animals. They are using various formulations of the gel to apply trametinib directly to skin tumors. The initial results look promising, Ozbun says, adding that the study is ongoing. She hopes to later repeat this pre-clinical study to test the gel against human genital warts and cervical precancers.
Finally, Ozbun plans to use a $4 million grant from the National Cancer Institute to further develop the treatment for people. She will study the cellular processes that the drug uses to make the tumors shrink. That work is expected to start in April.
“It [this gel] will be the first of its kind,” Ozbun says. “We don’t have any antivirals for HPVs.”
Paper Reference
“The antiviral effects of a MEK1/2 inhibitor promote tumor regression in a preclinical model of human papillomavirus infection-induced tumorigenesis” was published online on July 8, 2023, in Antiviral Research (https://www.sciencedirect.com/journal/antiviral-research). Authors are Adrian J. Luna, Jesse M. Young, Rosa T. Sterk, Virginie Bondu, Fred A. Schultz, Donna F. Kusewitt, Huining Kang, Michelle A. Ozbun.
About the Grants
The National Institute of Allergy and Infectious Disease at the National Institutes of Health is supporting the research reported in this publication under Award Number 1R21AI176571, Principal Investigator: Michelle A Ozbun, PhD. This work was also funded by the National Cancer Institute, Cancer Center Support Grant, under Award Number P30CA118100, Principal Investigator Yolanda Sanchez, PhD. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The UNM Comprehensive Cancer Center
The University of New Mexico Comprehensive Cancer Center is the Official Cancer Center of New Mexico and the only National Cancer Institute-designated Cancer Center in a 500-mile radius. Its 136 board-certified oncology specialty physicians include cancer surgeons in every specialty (abdominal, thoracic, bone and soft tissue, neurosurgery, genitourinary, gynecology, and head and neck cancers), adult and pediatric hematologists/medical oncologists, gynecologic oncologists, and radiation oncologists. They, along with more than 600 other cancer healthcare professionals (nurses, pharmacists, nutritionists, navigators, psychologists and social workers), provide treatment to 65% of New Mexico’s cancer patients from all across the state. And they partner with community health systems statewide to provide cancer care closer to home. In 2024 they treated more than 15,000 patients in almost 105,000 ambulatory clinic visits in addition to in-patient hospitalizations at UNM Hospital. A total of 2,075 patients participated in cancer clinical trials to study new cancer treatments that include tests of novel cancer prevention strategies and cancer genome sequencing. The more than 123 cancer research scientists affiliated with the UNM Cancer Center were awarded $38.3 million in federal and private grants and contracts for cancer research projects.
Website:
UNM Cancer Center Clinic: 505-272-4946
UNM Cancer Center Community and Media Relations: 505-548-0927
RSS