USU Lab Researches Targeted Therapies for Breast Cancer
Uniformed Services University Upadhyay Lab is researching targeted therapies for treatment of triple-negative breast cancer
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Upadhyay lab staff, from left to right: Harrison Rudd, Sheelu Varghese, Geeta Upadhyay, and Deepak Rohilla. (Photo credit: Tom Balfour, USU) |
May 16th, 2023 by Vivian Mason
Published medical reports say that active duty female service members develop breast cancer at a 20–40% higher rate than the general public. Breast cancer is often managed by an estrogen receptor modulation treatment called tamoxifen that blocks the activity of estrogen in the breast, stopping the growth of some breast tumors. More often than not, the tamoxifen treatment sees a positive response rate; however, there is a certain class of breast cancer that does not respond to the treatment. That’s where the Upadhyay Lab at the Uniformed Services University (USU) comes in.
In the Upadhyay lab at USU, National Institutes of Health-funded research focuses on developing targeted therapies that take advantage of the body’s immune system against novel abnormal molecules, or biomarkers, discovered in the lab for treatment of triple-negative breast cancer, or TNBC, which does not respond to tamoxifen.
Geeta Upadhyay, Ph.D., the namesake of the lab, is an associate professor in the Department of Pathology and in the Molecular and Cell Biology Graduate Program at USU’s School of Medicine. She has more than 20 years of experience in breast cancer research and in running her research lab. Upadhyay also works closely with the John P. Murtha Cancer Center at Walter Reed National Military Medical Center, and has nothing but praise for her research environment.
“I love being here at USU,” Upadhyay says. “The university’s incredibly successful with the number of research labs that it has. Faculty members are very dedicated and very resource oriented. We can collaborate, pool our knowledge, and share information that could lead to new discoveries.”
She also works closely with the USU-HJF (Henry M. Jackson Foundation for the Advancement of Military Medicine) Joint Office of Technology Transfer to secure intellectual property and patents to safeguard commercialization plans for these novel drugs.
“We have developed novel antibody reagents and cell-based therapeutics (including CAR-T),” Upadhyay says. “These reagents will be tested in clinical trials and hopefully soon used in safety and efficacy trials.”
Upadhyay continues on, explaining that triple negative breast cancer primarily affects young women, but mostly women of color.
“At a younger age, it affects all sorts of women, and there is no targeted therapy for this kind of cancer. Thus, there’s an urgent need to develop drugs against it. With surgery and chemotherapeutics,” she adds, “we’re trying to figure out if there are specific molecules that cause this cancer growth and if we can double up on new therapeutics to evict this specific molecule that is causing the cancer.”
Continuing, she speculates, “What do we use to find out what causes these cancer cells to grow to the specific biomarkers? Mouse models? Human cancer cells? Bioinformatics? Chemistry? We hope one day to be able to use these therapeutics on our patients.”
Repurposing old clinically approved drugs to target various TNBC targets is a novel method of understanding what causes these breast cancer cells to grow in specific ways, and Upadhyay says it comes with fewer side effects and leads to successful, low-cost drug development in a shorter amount of time. Medicinal plants containing various chemical compounds (e.g. flavonoids, alkaloids, phenols, essential oils, tannins, glycosides, lactones, etc.) play a very crucial role in combating various types of diseases and are also used in the drug development process because they have lesser side effects.
Currently in the Upadhyay Lab, a new kind of therapy known as “cell therapeutics” is being used to improve the immune system's ability to fight cancer.
“With this kind of therapy,” Upadhyay says, “our body has the innate capability to kill cancer cells and a natural ability to eliminate those cells.”
According to Upadhyay, scientists are currently trying to reteach our immune system or use effective immune systems that work.
“For example,” she explains, “T cells or T cytotoxic lymphocytes kill cancer cells in patients who have cancer that grows and grows. So, what my lab and others are trying to do is clean the patient’s T cells and reengineer them to express the killing molecules that will specifically recognize the cancer cells and destroy them.”
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Upadhyay Lab staff, from left to right: Harrison Rudd, Deepak Rohilla, Geeta Upadhyay, and Sheelu Varghese. |
So how is that done?
Well, the principle is very simple. T cells have two signals: The first signal is a warning sign that shows the presence of a potential enemy, and the second signal is a confirmation that tells the T cell to attack. Both signals are essential for the T cell to become fully activated and fight off the invaders effectively.
“Since the natural immune system isn’t expressing this specific type of T cell, we engineer it,” says Upadhyay. “We remove the patient’s T cells and put the two signals together.”
In an engineered T cell, these two signals are put into one single molecule. Then, this engineered T cell can be intravenously injected directly into the bloodstream and into the body or into the tumor itself.
Millions of these injected cells can specifically catch and kill the tumor cells at the same time.
“This revolutionary method can kill most kinds of tumors,” explains Upadhyay. “However, for other kinds of tumors, it doesn’t work very well. In our lab, we’re trying to understand why that is.”
Upadhyay says she’s always interested in the biomarker proteins that are unique to cancer cells because they make the tumor therapies specific.
“We were very lucky because we found a short form of the molecule called LY6K. It’s expressed on the cancer cells, but not on the normal cells.”
Continuing, Upadhyay adds that this kind of discovery may seem abnormal. “You might think, ‘how can such a molecule even exist?’” This protein, LY6K, is found only in the testes and is absent in the female body. This protein is only important in sperm function and is required for vital organ function. It’s a mystery as to why TNBC now expresses a sperm protein that helps support its growth.
“This class of proteins, known as cancer testis antigens, is a very attractive target for cancer immunotherapy,” says Upadhyay. “We thought we should target this protein in human breast cancer because it’s not important for vital organ function, but it’s very important for cell growth.”
There are many different angles to target this protein in cancer (including small, drug-like molecules, antibodies, or cell-based therapies that will target the LY6K protein). The Upadhyay Lab developed novel antibodies to target this protein, as well as T cell therapy using LY6K as a target. The idea is to somehow stop this protein from functioning. “And, this,” Upadhyay adds, “is one of the goals of our lab.”
Her research also examines the role of the LY6K family of proteins in cancer progression, immune escape, and survival outcome. Work is focused on understanding the LY6K action on TGF-ß (Transforming Growth Factor) and tumor immune escape pathways in breast cancer. The novel drug development aspect of this project is focused on testing the small molecule binders of LY6K in the treatment of TNBC.
Members of the Upadhyay Lab include Dr. Sheelu Varghese, Deepak Rohila (scientists), and molecular and cell biology graduate student Harrison Rudd. Each person has their own research project, but the entire team functions as a unit to try and unlock the mysteries of cancer cells so that the knowledge can be harnessed to find a cure.
Currently, the Upadhyay Lab collaborates with investigators at the Breast Care and Research Center at the Murtha Cancer Center; the National Cancer Institute; the National Center for Advancing Translational Sciences at the University of South Carolina; Harvard Medical School; and Georgetown University. Upadhyay herself couldn’t be more pleased with the amount of shared resources at her disposal.
“The thing I like about science is that you can collaborate with people and work with all types of individuals throughout the United States and all over the world,” she concludes. “Teamwork is very important because ideas come when you share information. That’s exciting to me.”
