Novel First-in-Class Cancer Drug in Clinical Trials at Sylvester
Summary
- Sylvester Comprehensive Cancer Center researchers are enrolling patients in the first clinical trial of the cancer drug EP31670.
- Sylvester’s trial site will join six other locations around the country, evaluating EP31670’s safety and determining proper dosing or the amount of drug that patients should receive.
- EP31670 inhibits two types of proteins that contribute to aberrant gene expression, qualifying it as a “first-in-class” medication.
An experimental cancer therapy with an unprecedented combination of activities is approaching a milestone at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, where it was discovered and developed. This month, researchers expect to begin enrolling patients in the first clinical trial of the cancer drug EP31670. This trial represents the next phase in a journey that began in the lab of Claes Wahlestedt, M.D., Ph.D., nearly 15 years ago.
“It’s very satisfying as a researcher to see a drug candidate move to the clinic where it can help people,” said Dr. Wahlestedt, professor of psychiatry and behavioral sciences, director of the Center for Therapeutic Innovation and associate dean for therapeutic innovation at the Miller School. “We talk about that all the time, but it’s a rare event.”
Once open, Sylvester’s trial site will join six other locations around the country, evaluating EP31670’s safety and determining proper dosing or the amount of drug that patients should receive. While other sites are enrolling patients with certain solid tumors, Sylvester’s site will focus on chronic or slow-progressing leukemias, including a blood cancer known as myelofibrosis.
EP31670’s anti-cancer activity stems from its ability to simultaneously inhibit two types of proteins that contribute to aberrant gene expression. No other single cancer therapy targets this combination, making EP31670 a “first-in-class” medication.
An Epigenetic Approach
EP31670’s targets, a group of proteins called BET and the duo CBP/p300, both have epigenetic activity. They regulate the expression of genes. Changes to the packaging of DNA, such as the presence of chemical tags, influence the degree to which the genetic code is available for translation into proteins that drive cancer. While CBP and p300 add these tags, BET proteins help cells interpret them.
Researchers have for some time sought to reprogram and deactivate cancer cells by manipulating these and other epigenetic regulators of cancer. In 2011, after learning about promising results from studies of inhibitors targeting either BET proteins or CBP/p300, Dr. Wahlestedt and his colleagues had an idea.
“There are drugs that do one or the other, but no drugs that could do both,” Dr. Wahlestedt said. “One of our hopes was that we could find a drug that does both.”
Roughly six years and 1,000 compounds later, they settled on a substance that would become EP31670. Not long afterward, experiments in cells in Sylvester’s labs demonstrated its detrimental effects on leukemia and other cancers.
From the Lab to the Bedside
This compound still had a long road to travel. Many promising drug candidates fail to make it to patients. This difficult period in the translation of discoveries into treatments is sometimes called the “valley of death.”
In 2021, after many additional tests of EP31670’s suitability as a drug, Dr. Wahlestedt’s group began to pursue the FDA’s approval to test it in clinical trials through an Investigational New Drug (IND) application.
In January 2022, the FDA approved the IND. There are now clinical trial sites in Texas, Massachusetts, Washington and at Sylvester in Miami.
Moving Forward with Cancer Patients
So far, 24 patients with leukemia or solid tumors have received EP31670. Sylvester’s site, which is run by principal investigator Terrence Bradley, M.D., assistant professor in the Division of Hematology and medical director of inpatient hematology at Sylvester, and program leader Justin Watts, M.D., associate professor in the Division of Hematology and chief of the leukemia section at Sylvester, focuses solely on chronic leukemias that affect the blood-producing cells in the bone marrow.
Myelofibrosis causes scarring of the bone marrow that interferes with the production of blood cells and causes debilitating symptoms, such as fever and bone pain. In time, myelofibrosis can turn into acute or fast-progressing leukemia.
EP31670’s targets — the BET proteins called BRD4 and CBP/p300 — control the expression of genes that can cause the progression of myelofibrosis, according to Dr. Watts. Other experimental BET inhibitors that inhibit only BRD4 have shown promise in treating myelofibrosis, a good sign for EP31670’s prospects as a dual inhibitor of BRD4 and CBP/p300, according to Dr. Watts.
In addition to its epigenetic activities, EP31670 has another advantage. Formulated as a pill taken once a day, it is convenient for patients, he said. While some myelofibrosis patients enrolled in the trial receive EP31670 alone, others take it along with another type of drug called a JAK inhibitor, which targets a different leukemia-driving pathway called JAK-STAT.
“It’s exciting to offer patients a new drug that has a novel mechanism of action in a disease that has poor outcomes,” Dr. Watts said. “We’ve got to change something, or we make little progress.”
Tags: cancer research, clinical trials, Department of Psychiatry and Behavioral Sciences, Dr. Claes Wahlestedt, Leukemia, myelofibrosis, Sylverster Comprehensive Cancer Center