Published by the Students of Johns Hopkins since 1896
May 23, 2024

Researchers breach blood-brain barrier

By ELAINE CHIAO | November 3, 2016

In the United States, brain cancer has historically had a high death rate, with 66.5 percent of patients dying within five years of their diagnoses.

Recently, scientists from Johns Hopkins Drug Discovery and the Bloomberg-Kimmel Institute for Cancer Immunotherapy seem to have discovered a turning point in the drug treatment for brain cancer.

Together, they have come up with an experimental drug that seems to be able to slip through the selectively impermeable blood-brain barrier.

The blood-brain barrier is essentially a filter that separates circulating blood from the extracellular fluids in the central nervous system (CNS). The barrier is vital to the human body because it protects the brain from foreign substances, big molecules and other harmful hormones.

The first experiments with this anti-cancer drug date back to the 1940s, when scientists back then first extracted the compound from Peruvian soil.

The drug was then named 6-diazo-5-oxo-L-norleucine or simply DON.

DON serves mainly to block the neurotransmitter glutamine, whose main role is to synthesize proteins.

A tumor is an abnormal growth of tissue that consumes all of the nutrients around it, which creates a negative environment in the body that weakens the immune cells’ ability to fight off cancer cells.

DON is efficient and effective in shrinking cancer tumors. However, it has a toxic side effect that disrupts the functions of the gastrointestinal system.

“We wondered whether we could make a safer and more tolerable form of DON by enhancing its brain penetration and limiting its exposure to the rest of the body and, thus, toxicity,” Barbara Slusher, currently a professor of neurology, medicine, psychiatry, neuroscience and oncology at the Hopkins School of Medicine said according to the press release.

Slusher, who is also the director of Johns Hopkins Drug Discovery, worked alongside The Sidney Kimmel Comprehensive Cancer Center immunologist Dr. Jonathan Powell, whose research primarily focuses on the relationship and interactions between cancer cells and immune cells.

Altering the chemical composition of DON is no easy task. Slusher and Powell must find a way to make the drug more lipid-soluble so that it can pass through the blood-brain barrier more easily.

Slusher and Powell are still trying to figure out whether drugs that block the transmission of glutamate could alter the environment near the tumor, making it more accessible to immune cells. This may be able to prevent or at least halt the growth of tumors, which can potentially give the body’s immune system a chance to wipe out the cancerous cells.

“The hope is to enhance certain immunotherapy drugs by adding such glutamine antagonists,” Powell said in a press release.

The scientists and their team from Johns Hopkins Drug Discovery and the Bloomberg-Kimmel Institute for Cancer Immunotherapy tested the efficiency of the altered DON by injecting it into monkeys and measuring the levels of DON in the monkeys’ plasma and cerebrospinal fluid. The researchers compared these values to the levels of DON in the cerebrospinal fluid and plasma of monkeys that were injected with unaltered DON.

They found that the altered, more lipophilic DON was able to pass through the blood-brain barrier into the cerebrospinal fluid 10 times better than the unaltered drug could.

The road to combating cancer is surely a long and tedious one. However, scientists like Slusher and Powell proved that they can modify anti-cancer drugs to ensure that they specifically target the brain and do not release toxic chemicals to the rest of the body.

The next step on the scientists’ agenda is to use the same principles that have allowed them to develop drugs that pass through the blood-brain barrier in order to develop drugs to fight other types of cancers in different parts of the body.

In the future, we may hope for cancer drugs that are tailored to target specific cancers.


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