A promising drug could lead to a new treatment for the most aggressive form of breast cancer, which affects thousands of women every year. A preclinical study led by the University of Adelaide found that the new drug successfully inhibits the growth of triple-negative breast cancer without toxic side effects.
The results of research were published in Oncogene.
Promising new therapy for aggressive breast cancer
“This is an exciting development in the battle against triple-negative breast cancer, which is the most aggressive form of the disease,” said Associate Professor Theresa Hickey, internationally recognized breast cancer expert at Dame Roma Mitchell Cancer Research Laboratories of the University of Adelaide.
“There is currently no treatment specifically targeted for this type of breast cancer, with chemotherapy and, in some women, immunotherapy being the only options. The results of this study show that this drug could be the key to improving survival rates.”
The drug is designed to be taken orally and works by targeting a specific protein in the cancerous tumor called CDK9, which accelerates cell growth. By inhibiting this protein, it effectively stops cancer in its tracks.
“Our preclinical study shows that the drug was able to stop the multiplication of tumor cells, but did not affect normal cells in breast tissue taken from patients. It is still early days, but based on this initial evidence, we believe that inhibiting this protein could lead to a treatment for triple-negative breast cancer and this new drug should be developed further,” Associate Professor Hickey said.
The collaborative study published in Oncogene also involved Professor Shudong Wang of the University of South Australia, who developed the drug (CDDD11-8) for the treatment of acute myeloid leukemia.
“We developed CDDD11-8 as a potent, selective, and orally bioactive CDK9 inhibitor for cancer therapy. We are very excited about its therapeutic potential against triple-negative breast cancer shown by Associate Professor Hickey,” Professor Wang said.
In Australia, approximately 2,500 women are diagnosed with triple-negative breast cancer each year. This type of breast cancer occurs more frequently in younger women. It has a higher rate of recurrence within five years and a higher mortality rate than other breast cancers during this period.
The researchers hope to identify biomarkers that predict which triple-negative breast cancers will respond best to the inhibitor drug so that these can be used to select patients for future studies.
“Although this drug is showing promise as a potential treatment for triple-negative breast cancer, it requires further development before it can move into human trials. I hope this will happen within the next five years, if not sooner,” said the Associate Professor. Hickey.
The researchers also plan to conduct future studies to explore whether this potential therapy could be used to treat other types of breast cancer.
“It is critical that we continue to research and preclinically evaluate targeted therapies for this aggressive disease and improve the outlook for all breast cancer patients,” Associate Professor Hickey said.
Cleveland Clinic researchers have successfully developed a therapeutic peptide that prevents aggressive cancer cells from multiplying rapidly. The findings highlight a potential new strategy for developing targeted treatments for triple-negative breast cancer, which currently has no approved options.
Targeted drugs directly attack the functions of tumor cells, offering a more precise approach to complement broader treatments such as chemotherapy. A research team led by Ofer Reizes, Ph.D., and Justin Lathia, Ph.D., has designed a therapeutic peptide that disrupts the molecular processes underlying aggressive cancer growth when administered into cells.
The drug blocked cancer growth and induced tumor cell death and affected cancer cells only in preclinical work. The study was highlighted in Molecular Cancer Therapeutics.
“It's devastating that we currently have such limited options to help people with triple-negative breast cancer,” says Dr. Reizes, Laura J. Fogarty Chair in Uterine Cancer Research. “We want our findings to offer hope to these patients and their families and serve as a starting point for bringing more treatments into the development pipeline.”
Peptides are short proteins made up of amino acids that form the “building blocks” of larger proteins. Natural and artificially synthesized proteins are commonly used to treat diseases. Some peptides are used to supplement existing proteins in the body, such as insulin in people with diabetes.
The peptide in development, based on a 2018 Cleveland Clinic discovery, serves as a proof of concept for this type of triple-negative breast cancer drug.
Because triple-negative breast cancer cells lack certain receptors, drugs designed to treat other subtypes of breast cancer will not work. There are currently no targeted drugs approved for triple-negative breast cancer, which makes up 15% of breast cancer cases. To develop new drugs, researchers needed to identify new effective targets.
A previous postdoctoral researcher with Dr. Reizes and Dr. Lathia's team found that Cx26, a type of protein called connexin, forms a molecular complex in triple-negative breast cancer cells that makes them more likely to relapse or spread throughout the body. Researchers have been working to find a way to disrupt that complex, which would limit the cells' cancerous properties.
First authors Erin Mulkearns-Hubert, Ph.D., and Emily Esakov Rhoades, Ph.D., developed a therapeutic peptide. The sequence of the peptide is the same as the Cx26 component necessary for the formation of the complex. The goal is to saturate the system with the peptide and disrupt the ability of integral proteins to bind, says Dr
. Mulkearns-Hubert, a research associate in the Lathia lab.
“The design of the peptide was actually relatively simple and it worked beautifully, slowing tumor growth in preclinical models,” he says. “Triple-negative breast cancer remains an incredibly difficult tumor type to treat, so the development and testing of strategies like this peptide is critical moving forward.”
The researchers observed that the drug prevented cancer stem cells present in a capsule from self-renewing, a characteristic of aggressive cancer cells that supports resistance to treatment. The team is now working with Cleveland Clinic Innovations to develop the drug and explore the potential for clinical trials.
Researchers from the Center for Genomic Regulation and the Vall d'Hebron Institute of Oncology have shown that the simultaneous inhibition of two different proteins may represent a new strategy to tackle triple-negative breast cancer, the most aggressive form of breast cancer and drug resistant. The results were published today in the journal EMBO Molecular Medicine.
Breast cancer is the most commonly diagnosed type of cancer and the fourth most common cause of cancer-related death in women, with more than two million cases worldwide and 685,000 deaths in 2020.
About one in seven (15%) of these cases are a highly aggressive form of the disease known as triple-negative breast cancer. The prognosis for triple-negative breast cancer is poor. The disease is highly resistant to existing treatments because its cells lack the receptors targeted by breast cancer drugs.
The LOXL2 enzyme was recently shown to drive the growth of triple-negative breast cancer. A team led by Dr. Sara Sdelci of the Genomic Regulation Center and Dr. Sandra Peiró, together with researchers from the Upper Gastrointestinal Cancer Translational Research Group of the Vall d'Hebron Oncology Institute, carried out various analyzes to evaluate the suitability of the enzyme as a biomarker capable of predicting treatment outcome.
They found that LOXL2 expression could only predict the outcomes of drugs that target the BRD4 protein, a known cancer trigger. Driven by the interest of their findings, the researchers carried out further experiments to evaluate whether LOXL2 and BRD4 might work together to help triple-negative breast cancer cells grow.
Various laboratory experimental techniques have demonstrated that LOXL2 interacts with a version of BRD4 within the nucleus. Researchers have shown that this interaction changes the expression of genes and ultimately helps triple-negative breast cancer cells grow. Simultaneous inhibition of both proteins disrupted these interactions and helped slow cancer growth in cell cultures (in vitro) and in three separate mouse models (in vivo).
“Our in-depth investigation into how triple-negative breast cancer cells grow at the molecular level has revealed a new mechanism that can be exploited for therapeutic purposes. It's exciting because a two-pronged strategy that targets both proteins could be combined with other treatments and transform triple-negative breast cancer from a disease with a very poor prognosis to a manageable disease,” says Dr. Laura Pascual Reguant, first author of the study and postdoctoral researcher at the Center for Genomic Regulation in Barcelona.
The findings have important implications for an experimental class of drugs known as BET inhibitors, which have shown promise in the fight against triple-negative breast cancer. BET inhibitors work by impairing BRD4 function, but have failed to make it past the clinical trial stage because triple-negative breast cancer cells acquire resistance. The study authors believe that targeting both BRD4 and LOXL2 simultaneously could help overcome this resistance.
The next challenge will be finding how to safely and effectively target both proteins at the same time. One way is to combine existing inhibitors. Different versions of BRD4 are already targeted by BET inhibitors in 30 different clinical trials, five of which involve triple-negative breast cancer. LOXL2 inhibitors also exist, but their safety and effectiveness in treating cancer has not been explored. The combination of both inhibitors has not been tested.
“More work needs to be done before our findings can benefit patients, but any progress in understanding the mechanisms of this highly aggressive disease is good news. As we continue to shed light on how triple-negative breast cancer grows, the health challenges it poses may be more treatable than we initially thought,” concludes Dr. Sdelci.
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