Scientists at the University of Chicago have discovered a new class of drug compounds to potentially treat FOXM1positive breast cancer. This would be the first known type of drug to treat the FOXM1 mutation, and the new compounds have been shown to suppress tumor growth in preclinical breast tumor models, though clinical trials have not yet been started.
The researchers in this study decided to focus on finding potential FOXM1 therapeutic agents when they began their screen for compounds because FOXM1 is found in higher abundance in cancer cells than in healthy human cells, said Benita Katzenellenbogen, a University of Illinois professor who led the study with colleagues John Katzenellenbogen and Yvonne Ziegler.
This naturally occurring protein plays an important role during early development, but normally is present only at very low levels in adult tissues.
Transcription factor FOXM1 is often upregulated and overexpressed in aggressive, therapy-resistant forms of hormone receptor-positive and triple negative breast cancers, among other cancer types. It is associated with poor patient survival rates, and can control several downstream genes that impact cancer cell division, aggressiveness, and metastasis. The presence of FOXM1 is also correlated with resistance to radiation and many chemotherapies in several subtypes of breast cancer.
“FOXM1 is a key factor that makes breast cancer and many other cancers more aggressive and more difficult to treat,” Benita Katzenellenbogen said. “Because it is a master regulator of cancer growth and metastasis, there has been great interest in developing compounds that would be effective in blocking it.”
So far, no previous drug agents have been successfully developed to reduce the effects of FOXM1, John Katzenellenbogen said. “There are reports of other inhibitors of FOXM1, but these are generally less potent and do not work well in the body.”
Katzenellenbogen and colleagues synthesized and characterized a library of compounds specifically designed to target FOXM1, and after an intensive screening process for potential compounds, a new class of drugs showed some positive preliminarily results: 1,1-diarylethylene mono-and diamine compounds. The new drugs were analyzed for various properties and selected based on ability to reduced breast cancer cell proliferation and inhibit the expression of genes known to be regulated by FOXM1.
The team then modified the compounds to enhance their ability to inhibit FOXM1and increase the cellular potency of the chemical. Three of the tested compounds were then selected as the best performers. Each drug would bind to FOXM1and label it for degradation by the cell, thus reducing its negative effects.
“Our compounds have good anti-tumor activity in animal models. They behave well in vivoand have long half-lives in the blood. Some work well when given orally, which is desirable for ultimate patient use,” John Katzenellenbogen added.
“We found that these compounds inhibit the growth of breast cancer cells that represent the major subtypes of breast cancers, including estrogen receptor-positive, HER2-positive and triple-negative breast cancers,” Benita Katzenellenbogen said. “They also block the growth of human breast tumors in mouse models.”
The research is promising, but preliminary, the scientists said. It usually takes several years for potential drug compounds to go from this stage of laboratory experiments to clinical trials in humans, but starting with favorable pharmacokinetic properties should hopefully speed up the process.
“Because cancers are often treated with a combination of drugs, we are exploring how our FOXM1inhibitors might be combined with other standard-of-care agents to improve cancer treatment,” Benita Katzenellenbogen said.
While these compounds were observed to be effective antitumor agents when administered alone and at low doses in several breast cancer subtypes, cancer drugs are rarely given as a single treatment to a patient, so it will be very interesting to test them in combination with standard-of-care combination treatments targeting ER-positive, recurrent, metastatic, endocrine therapy-resistant breast cancers and aggressive triple negative breast cancers. It will also be interesting to see a possible synergistic effect in patient populations when and if these drugs make it to trials.
