Israelis test first targeted multi-drug cancer therapy

Scientists say the treatment could one day make cancer drugs more potent with fewer side effects

An illustration of a cancer cell. (photo credit: Cancer image)
An illustration of a cancer cell. (photo credit: Cancer image)

Delivering cancer-fighting drugs directly to malignant cells is the best way to fight the deadly disease, and Israeli scientists are working on a better way to do that — linking multiple drugs to a chemical engine that can drive them exactly where they need to go.

The process, so far proven only on mouse cells, uses tiny molecules called peptides to carry cancer drugs into specific cancer cells. In a study published in the European Journal of Medicinal Chemistry, the scientists showed that the treatment can deliver two different drugs at once, killing leukemia cells while leaving healthy cells undamaged.

No targeted cancer therapy on the market can deliver more than one drug at once. The scientists say the experimental treatment also appears to be more targeted than existing types. With these advantages, they say, the treatment could make existing cancer drugs deadlier to cancers while at the same time reducing their side effects.

Clinical trials are at least two years away.

“We are talking about a technology for targeted drug delivery that consists of a special platform and multiple drugs that are linked to the platform,” said Prof. Gary Gellerman, a biochemist, who built the “peptide-drug conjugates” along with Prof. Michael Firer, a biotechnologist at Ariel University, who developed the drugs. “The advantages for patients are that we can direct more of the drugs to where they are supposed to go, with no side effects. For the first time, we can target cancer with multiple drugs at once.”

Gary Gellerman, a biochemist at Ariel University. (photo credit: Courtesy)
Prof. Gary Gellerman, a biochemist at Ariel University, who coauthored the study. (photo credit: Courtesy)

So far, the scientists are focusing on leukemia, prostate cancer, and lung cancer, but they say the treatment should work with any type of cancer.

Prof. Robert Langer, a biomedical engineer and a leading researcher of cancer drug delivery at the MIT, called the study “very interesting.” He said “a key next step is to see how it works in vivo [in animals] from a safety and efficacy standpoint.”

Up close and personal

Chemotherapy, the drug treatment for many types of cancer, works by killing all actively dividing cells. Because cancer cells divide so quickly, they are dealt the biggest blow. But healthy cells are also damaged, particularly fast-dividing ones, like bone marrow, blood, and hair follicles. The resulting side effects, like weakened immunity, anemia, and hair loss, can be deadly, and so treatment options are limited.

‘We’ve got this cargo of drugs that we want to take into the cell, and we want to put it onto a truck that’s going to going to go to one particular address’

In the past two decades, targeted cancer therapies have been developed to act specifically on molecules involved in cancer growth. Among these treatments are “carrier-drug conjugates,” carrier molecules chemically attached to cancer drugs.

The conjugates are chemically engineered to bind to and to enter only specific cancer cells, where they release the drugs. The carrier, the drug, and the attaching “bridge” can each be matched to the cancer they are meant to target — an example of highly personalized medicine.

A variety of molecules can be used as carriers. Most research is now focused on conjugates with antibody carriers, but some researchers have concluded that peptides are better for the future.

“We’ve got this cargo of drugs that we want to take into the cell, and we want to put it onto a truck that’s going to going to go to one particular address,” Firer said. “The question is what is the most effective and efficient truck. We use peptides, which are more flexible, cheaper, and easier to produce. We can make them more specific to the cancer we want to target.”

Prof. Michael Firer, a biotechnologist at Ariel University. (photo credit: Courtesy)
Prof. Michael Firer, a biotechnologist at Ariel University, who coauthored the study. (photo credit: Courtesy)

Firer and Gellerman have been chemically engineering peptide-drug conjugates at Ariel University for several years. Their latest study focuses on cancer drugs, another part of the conjugates.

Flipping the switch on cancer

To test their treatment’s ability to activate drugs only in target cancer cells, the scientists put five drugs known or thought to treat multiple myeloma, a type of leukemia, in contact with two types of cells: mouse leukemia cells and healthy mouse cells. As expected, the unconjugated drugs killed both types of cells.

Next, the scientists created new peptide-drug conjugates by attaching the drugs to peptides known to bind to leukemia cells. They designed the bridges between the peptides and the drugs to “switch off” the drugs. The bridges were to break down and “switch on” the drugs only in specific chemical environments within the leukemia cells, where they were predicted to be most effective.

In the final stage, the scientists put the conjugates back in contact with the two groups of mouse cells. This time, the conjugates killed the cancer cells, but they did no damage to the healthy cells.

The results indicate that the conjugates can activate at least two different drugs at target locations within target cells. Bundled into conjugates with peptides that bind only to those cells, the drugs could one day provide a new level of targeted cancer treatment for people, the scientists say. They are working on adding more drugs to the conjugates. The next step, they say, is to test the conjugates on mice with leukemia.

With high precision and low side effects, the scientists say, the conjugates could make cancer drugs already on the market more effective and give new life to cancer drugs that were shelved for being too toxic.

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