A peptide that successfully targeted and killed metastatic cancer cells in mice may open the door to developing more efficient ways to detect and treat metastatic breast cancer in humans, UTHealth Houston researchers have discovered.

The research was published in Molecular Therapy Oncology and led by Mikhail Kolonin, PhD, director of the Centre for Metabolic and Degenerative Diseases in The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases at McGovern Medical School at UTHealth Houston.

Metastasis, the spread of cancer from its original site to other locations in the body, is the leading cause of death for cancer patients.

It’s difficult to treat cancer once it has spread, and there are currently no drugs available that target metastatic cells.

Kolonin and his team were focused specifically on triple-negative breast cancer, an aggressive form of breast cancer that is common among young women and accounts for about 10 to 15% of all breast cancers, according to the American Cancer Society.

“There are lots of drugs against breast cancer that work for a while to suppress the growth of primary tumours. But once the cancer metastasizes, especially the aggressive types of breast cancer such as triple-negative breast cancer, then it's really hard to treat,” said Kolonin, who is also the Harry E. Bovay, Jr. Distinguished University Chair in Metabolic Disease Research at McGovern Medical School.

“Most drugs that are available will kill both primary tumour cells and maybe some metastatic cells, but they also have broad toxicity and lots of side effects.”

To tackle this problem, Kolonin and his team focused on the peptide BLMP6, which sticks to metastatic breast cancer cells.

When researchers attached a glowing dye to BLMP6 and injected it into mice grafted with triple-negative breast cancer cells, they found that the peptide travelled directly to metastatic cells.

Researchers then used an FDA-approved cytotoxic drug, monomethyl auristatin E, and attached it to BLMP6.

Mice injected with the peptide-drug conjugate showed suppressed metastasis and improved survival rates.

Kolonin and his team also used computer modelling based on artificial intelligence to find out that BLMP6 binds to a protein known as fibulin-4.

That protein is expressed at high levels in metastatic breast cancers.

The team used AI to predict BLMP6 binding to human fibulin-4 and demonstrated that the results seen in mice could be translated clinically by confirming that BLMP6 targets human breast cancer cells.

“We used an array of human tissues that were collected from patients with various types of breast cancer – noninvasive and invasive,” Kolonin said.

“What we found was that there was a pretty clear correlation of BLMP6 peptide binding to aggressive, invasive breast cancers, but not to the cells of noninvasive breast cancer or normal breast tissue.”

The discovery indicates that fibulin-4 is a “target” on premetastatic tumours, paving the way for researchers to develop therapies that can specifically seek out and destroy spreading cancer cells.

“There is efficacy of both the BLMP6-drug conjugate and BLMP6-based imaging probes useful for metastasis detection that we demonstrated in preclinical cancer models. This is really exciting,” Kolonin said.

Researchers from the Institute of Molecular Medicine include Alexes Daquinag; Sheng Zhang, PhD; Zhiqiang An, PhD; Ali Azhdarinia, PhD; Sukhen Ghosh; Stephen Farmer; and Ashwin Kumar Ramesh.

Additional authors include Solmaz AghaAmiri, PhD, of Tempus AI and Servando Hernandez Vargas, PhD, of the National Centre for Tumour Diseases Dresden, Germany.

Photo by UTHealth Houston

Source: University of Texas Health Science Center at Houston