LOWVELO Impact: riders helping fund research to fight triple-negative breast cancer
LOWVELO is a physical way to do something to help the people we love battling cancer and to make life better for future patients. It’s all about funding lifesaving cancer research at MUSC Hollings Cancer Center. As South Carolina’s only National Cancer Institute-designated cancer center, the innovative research happening at Hollings impacts patients across the state and beyond.
One of the people behind that lifesaving research is Philip Howe, Ph.D., professor and chair of the Department of Biochemistry and Molecular Biology, and co-leader of the Hollings Cancer Biology & Immunology program. Thanks to funding raised by LOWVELO riders, Howe’s research has the potential to change treatment strategies for patients with triple-negative breast cancer. We sat down with him recently to learn more about his LOWVELO-funded research.
"My message to the riders, donors and volunteers who take part in LOWVELO is a simple one: Your support and effort allows MUSC Hollings Cancer Center to fund research that might not otherwise be supported. LOWVELO funding allows for high risk/high reward discoveries."
-Philip Howe, Ph.D.
Can you start by giving us a little background about yourself and your work at MUSC Hollings Cancer Center?
My name is Philip H. Howe and I am a professor and chair in the Department of Biochemistry and Molecular Biology and a co-leader of the Cancer Biology & Immunology program at Hollings Cancer Center. I joined MUSC 13 years ago after having spent 21 years at the Cleveland Clinic and Case Western Reserve University. I currently have an active research program focused on breast cancer that has been continuously funded by the National Cancer Institute for over 33 years. As departmental chair, I am responsible for the day-to-day operations of an academic medical department whose responsibilities involve teaching and basic science research.
How did you get your start or find an interest in the field of cancer research?
As a child, I often took my toys and other things apart to try to figure out how they worked. This curiosity led, during my formative years, into the study of biology and biochemistry and eventually in my obtaining a Ph.D. in biochemistry and molecular biology. As a postdoctoral fellow at Vanderbilt University, I began to study basic mechanisms that control cellular growth and as these types of studies often involve comparative analyses between normal and transformed cells, my interest naturally evolved into the field of cancer.
Can you tell us about your Small Molecule Inhibitor of ARIH1 project? How did you discover a need for this research? What are you hoping to achieve through the project?
Chemotherapy is the standard of care in metastatic triple-negative breast cancer. Unfortunately, this treatment strategy results in low rates of complete response and the development of recurrent disease.
In our previous studies, we discovered that a protein called ARIH1 plays a crucial role in regulating epithelial cell growth. Epithelial cells are a type of cell that cover the inside and outside surfaces of your body. These cells are found on your skin, blood vessels and organs and help your body with things like protection, secretion, absorption, excretion, filtration, diffusion, and sensory reception.
ARIH1 helps regulate normal cell cycle progression, but in triple-negative breast cancer cells, ARIH1 levels are elevated. This causes a breakdown in the regulatory proteins that help control cell growth.
So, we reasoned that if we could develop a drug that could bind to and help the ARIH1s function properly, then we could potentially develop a therapeutic for triple-negative breast cancer. For this we performed a virtual screen and identified small molecules that could bind to ARIH1 to silence cell invasion and improve chemo response.
These small molecules were then tested in in vitro studies in cells to confirm they would bind with ARIH1 and stop impairing key cell cycle regulators. Through these analyses we identified a small molecule inhibitor of ARIH1, called A3, that when applied to cells in culture could lead to the death of cancer and not normal cells.
When did you find out that your project was receiving funding from LOWVELO and how much did you receive?
We obtained funding from LOWVELO in the fall of 2021. As mentioned, this grant allowed us to perform the initial virtual screen to identify small molecules that could bind to ARIH1 and to test whether they could inhibit ARIH1 function in in vitro analyses.
Where are you now in your work/project and what are you seeing so far?
Since the original isolation and identification of compound A3, we have performed synthetic chemistry and modification of A3 in order to develop a “better” drug with respect to potency and specificity for cancer cells. We initiated pharmacokinetic studies with our derivative A3 molecules to optimize absorption, distribution, metabolism and excretion. We were also able to secure funding for these studies from the Department of Defense (Breast Cancer Initiative) for a 3-year $1,000,000 award. We are quite excited in that we have been able to identify several A3 derivatives that are 10-100 fold more potent than the original A3 in their specific killing of triple-negative breast cancer, and not normal breast epithelial cells.
What does it mean to you to have your project funded in this way?
The LOWVELO funding allowed us the initial support for this project. As mentioned, this project was based on the simple hypothesis, based upon our previous studies, that an inhibitor of ARIH1 might prove to be an effective therapeutic for triple-negative breast cancer. These types of high risk/high reward projects, based upon a simple and unproven hypothesis, are seldom funded through the usual funding agencies and rely on developmental funds as provided by charities such as LOWVELO. So, LOWVELO funding was essential to this project.
What would your message be to the riders, volunteers and donors who take part in LOWVELO and helped make this funding possible?
My message to the riders, donors and volunteers who take part in LOWVELO is a simple one: Your support and effort allows MUSC Hollings Cancer Center to fund research that might not otherwise be supported by other extramural funding agencies. LOWVELO funding allows for high risk/high reward discoveries to be initiated with the hope that novel and effective therapeutics and protocols for cancer treatment can be developed.
