Experimental Peptide May Fight Multiple Cancer Types

A novel Mcl-1 protein inhibitor may encourage cancer cell apoptosis.

Scientists have developed a novel peptide that is able to disrupt a protein crucial to the survival of many types of cancer, including lymphoma, leukemia, and breast cancer, according to a study published by the Proceedings of the National Academy of Sciences.

The Mcl-1 protein helps cancer cells avoid programmed cell death resulting from DNA damage. By inhibiting this protein, the experimental peptide can force cancer cells to die.

“Some cancer cells are very dependent on Mcl-1, which is the last line of defense keeping the cell from dying. It’s a very attractive target,” said senior author Amy Keating, PhD.

Mcl-1 and 5 related proteins are overactive in cancers and form an apoptotic blockade, meaning that cancer cells avoid apoptosis even when they experience DNA damage.

“Cancer cells have many strategies to stay alive, and Mcl-1 is an important factor for a lot of acute myeloid leukemias and lymphomas and some solid tissue cancers like breast cancers,” Dr Keating said. “Expression of Mcl-1 is upregulated in many cancers, and it was seen to be upregulated as a resistance factor to chemotherapies.”

Developing treatments that target the Mcl-1 protein have been notoriously difficult because the interaction between Mcl-1 and its target protein occurs in a stretch of 20 to 25 amino acids, according to the authors. Inhibiting an interaction this long is difficult to do with small molecule drugs, according to the study.

Peptides have been of interest to researchers due to the ability to tightly bind with Mcl-1 and prevent it from binding with its target protein; however, peptides are typically not stable enough to use as drugs.

In the new study, the investigators had to figure out how to get the peptides to infiltrate cancer cells.

“We were exploring ways of developing peptides that bind selectively, and we were very successful at that, but then we confronted the problem that our short, 23-residue peptides are not promising therapeutic candidates primarily because they cannot get into cells,” Dr Keating said.

The study authors said that “stapling” peptides together with hydrocarbons that form crosslinks within the peptides can increase stabilization and help the molecules enter cells.

The authors developed 40 variants of the Mcl-1-inhibiting peptides and identified a location in the peptide where a “staple” increases stability, helps it enter cells, and binds more tightly to Mcl-1, according to the study.

“The original goal of the staple was to get the peptide into the cell, but it turns out the staple can also enhance the binding and enhance the specificity,” Dr Keating said. “We weren’t expecting that.”

The authors then tested the top Mcl-1 inhibitor candidates and found the drugs were able to kill cancer cells without the addition of another drug. The inhibitors were also observed to selectively kill Mcl-1-dependent cells and not those that rely on other members of the protein family, according to the study.

The researchers noted that additional testing is needed to determine the efficacy of the drug for specific cancers and whether it should be used as a monotherapy or in a combination treatment. Further studies should also explore whether the peptides can be used as a first-line therapy or for drug-resistant disease, according to the authors.

“Our goal has been to do enough proof-of-principle that people will accept that stapled peptides can get into cells and act on important targets. The question now is whether there might be any animal studies done with our peptide that would provide further validation,” Dr Keating said.