Tumour-invading protein delivers therapy straight to the brain

A novel protein designed by Cedars-Sinai Cancer investigators can cross the protective blood–brain barrier safely and deliver therapy directly into cancerous tumour cells. The team’s findings, which could help clinicians target brain tumours previously unreachable by chemotherapy, have been published in the journal Nature Nanotechnology.

The blood–brain barrier stops harmful particles from travelling from the bloodstream to the brain, but it also blocks therapeutic agents such as chemotherapy. Professor Lali Medina-Kauwe, Associate Director of Basic Research at Cedars-Sinai Cancer, and her team found that a protein called HER3 is present on the blood–brain barrier, and that it helps their tumour-invading protein cross from the bloodstream to the brain.

The investigators conducted experiments using a blood–brain barrier ‘organ chip’. In this laboratory device, small groups of induced pluripotent stem cells are transformed into blood vessel cells and brain cells and put in compartments in a pattern that mimics what happens in the human brain.

When investigators flowed their protein through the blood vessel portion of the chip, they saw that it crossed over and accumulated in the brain matter. When they blocked HER3 proteins in the chip, their proteins did not cross over, which suggests that HER3 aids their passage from the bloodstream into the brain.

“These blood–brain barrier organ chips are the next best thing to experiments in humans,” said study co-author Dr Clive Svendsen. “They allow us to create the ideal conditions for testing therapies such as this one. We can even use the patient’s own stem cells and make personalised organ chips to test how the drug may work for each person.”

The HER3 protein is also present on the surface of many types of cancer cells — especially in tumours that have spread from another part of the body to the brain. And the investigators’ experiments in laboratory mice showed that tumour-invading proteins directly targeted these HER3-positive tumours, reducing their growth without accumulating in other organs.

“Most cancer drugs enter healthy cells as well as cancerous cells, causing major side effects, but this tumour-invading protein selectively enters tumour cells and spares the healthy cells,” said study co-author Associate Professor Ravinder Abrol, a member of the Cancer Biology Program at Cedars-Sinai. “Our ability to actively target tumour cells is a major step toward cancer therapies with reduced toxicity and enhanced safety profiles.”

Once the protein enters tumour cells, it has the ability to evade their defences. Medina-Kauwe explained, “Most cells, including tumour cells, encapsulate invading particles in a bubble that allows the cell to harmlessly digest them. Our tumour-invading protein includes a pinwheel-like structure that prevents digestion. When our protein enters the unique environment of the tumour cell, it opens this pinwheel and breaks out of the bubble. When we pair the protein with chemotherapy, it can deliver a lethal blow.”

Medina-Kauwe said the findings are a step towards developing therapies that can deliver treatment to advanced tumours that currently have no other clinical option.

“We are finding that more and more tumour types — including breast, lung and colorectal tumours, and metastatic melanoma, as well as many primary brain tumours — are HER3 positive,” she said. “We’re looking forward to pursuing further studies to determine whether we can develop treatments for these tumour types.”

Image courtesy of the Medina-Kauwe Lab.