Finding Answers for Glioblastoma
Miller School of Medicine M.D./Ph.D. student Anna Hudson is using a National Cancer Institute grant to study an ancient virus’ impact on the most common type of brain cancer.
There is an ongoing cancer therapy revolution. Targeted therapies, which inhibit cancer-driving molecules, and immunotherapies, which unleash immune cells against tumors, have made significant gains against many cancers.
Glioblastoma (GBM), unfortunately, is an exception.
The most common brain cancer, GBMs are diffuse tumors that resist both manmade treatments and the body’s immune response. The median survival is around 15 months. Only 5% make it past five years.
Researchers at the University of Miami Miller School of Medicine, and around the world, have been working diligently to figure out this deadly tumor. They’re making progress. To increase this momentum, the National Cancer Institute (NCI) recently approved a prestigious NCI F30 grant for fifth-year M.D./Ph.D. student Anna Hudson. With this funding, she will study how an ancient virus, HERV-K, helps GBMs resist the immune response.
“We need to find better ways to encourage the immune system to overcome GBM resistance and attack tumors,” said Hudson. “HERV-K is a viable therapeutic target, so we need to understand how it functions and ultimately how we can inhibit it.”
A Sleeping Retrovirus
HERV-K is an endogenous retrovirus, a gene that originated in a virus but found its way into primate genomes millions of years ago. These ancient retroviruses make up around 8% of the human genome. Most of the time, HERV-K does nothing. The body has ways of silencing these nuisance genes. However, GBM and other cancers overexpress HERV-K to perform tumor-friendly functions and possibly tone down the immune response.
On a biological level, this makes perfect sense. HERV-K codes for an envelope protein, which decorates viral walls and performs a number of tasks, including debilitating immune cells.
“The HERV-K envelope inhibits T-cell proliferation and alters cytokine (immune signaling molecule) expression when it’s overexpressed,” said Hudson, “It can also drive tumor engraftment, which could be one of the reasons these cancers are so invasive.”
Hudson is trying to figure out the details of these interactions: how HERV-K interferes with T cells, how it actually binds to immune cells and how these interactions alter the overall immune response. But on an even bigger level, she’s trying to understand the tumor microenvironment—immune and other cells that protect tumors and encourage their growth.
“By exploring these endogenous retroviruses, we can better understand why the GBM microenvironment is so immunosuppressive,” said Hudson. “But also, learning more about how this tumor microenvironment works could give us clues to why immunotherapies have been ineffective against these tumors.”
Dual Mentors
Hudson is working with Ashish Shah, M.D., assistant professor of neurological surgery at the Miller School and one of Hudson’s mentors, on the STARLITE trial. The study repurposes antiretroviral medications, which are known to go to the brain, to decrease HERV-K levels. These drugs are being combined with laser interstitial thermal therapy, which uses laser-generated heat to recruit immune cells, to help GBM patients who are not eligible for surgery. This combination also has great potential to enhance standard-of-care therapies, such as chemotherapy and radiation.
“Anna is an amazing M.D./Ph.D. student who is driven to understand and dissect the immunosuppressive GBM microenvironment,” said Dr. Shah. “She has also developed novel techniques to show which brain tumors express HERV-K and assess the role T cells play in the tumor microenvironment.”
Hudson is also working closely with Thomas Malek, Ph.D., professor and chair of the Miller School’s Department of Microbiology and Immunology, whose mentorship has helped her interrogate the immune system and see how it can be harnessed to attack GBMs.
“Anna brings a new perspective to my group,” said Dr. Malek. “We are happy to help her and Dr. Shah move this important work forward.”
For Hudson, these two research experiences help her see the problem from different perspectives, hopefully providing insights that will lead to new therapies against these complex tumors.
“Dr. Shah is the GBM expert, and Dr. Malek has incredible immunology expertise,” said Hudson. “It gives me a really well-rounded view of the biology so we can learn more about the tumor microenvironment that protects GBMs and find better ways to overcome it.”
Tags: brain cancer, cancer research, Department of Medical Education, Dr. Ashish Shah, Dr. Thomas Malek, glioblastoma multiforme, glioblastoma research, glioblastomas, M.D./M.P.H. Program, medical education, NCI grant, Newsroom