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LOS ANGELES (Feb. 21, 2025) -- A unique protein designed by  investigators can cross the protective blood-brain barrier safely and deliver therapy directly into cancerous tumor cells, a preclinical study shows. The findings, which could help clinicians target brain tumors previously unreachable by chemotherapy, have been published in the peer-reviewed journal .

“One of the most challenging tumors to treat is cancer that has spread to the brain,” said , associate director of Basic Research at Cedars-Sinai Cancer, professor of Biomedical Sciences, and senior author of the study. “Our findings show that our tumor-invading protein can deliver a potent payload of therapy directly to these tumors. It is like a cancer smart bomb.”

A challenge in delivering chemotherapy to brain tumors has been the blood-brain barrier, which stops harmful particles from traveling from the bloodstream to the brain but also blocks therapeutic agents. Medina-Kauwe and team found that a protein called HER3 is present on the blood-brain barrier, and that it helps their tumor-invading protein cross from the bloodstream to the brain.

The investigators conducted experiments using a unique 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, Medina-Kauwe said. And when they blocked HER3 proteins in the chip, tumor-invading 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 , executive director of the Board of Governors Regenerative Medicine Institute at Cedars-Sinai and a co-author of the study. “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 personalized 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 tumors that have spread from another part of the body to the brain. And the investigators’ experiments in laboratory mice showed that tumor-invading proteins directly targeted these HER3-positive tumors, 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 tumor-invading protein selectively enters tumor cells and spares the healthy cells,” said study co-author Ravinder Abrol, PhD, associate professor of Chemistry and Biochemistry at California State University, Northridge (CSUN), and member of the Cancer Biology Program at Cedars-Sinai. “Our ability to actively target tumor cells is a major step toward cancer therapies with reduced toxicity and enhanced safety profiles.”

Once the protein enters tumor cells, a unique feature allows it to evade their defenses.

“Most cells, including tumor cells, encapsulate invading particles in a bubble that allows the cell to harmlessly digest them,” Medina-Kauwe said. “Our tumor-invading protein includes a pinwheel-like structure that prevents digestion. When our protein enters the unique environment of the tumor 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 promising and are a step toward developing therapies that can deliver treatment to advanced tumors that currently have no other clinical option.

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

Additional Cedars-Sinai Authors: Felix Alonso-Valenteen, Simoun Mikhael, HongQiang Wang, Jessica Sims, Michael Taguiam, James Teh, Sam Sances, Michelle Wong, Tianxin Miao, Dustin Srinivas, Nelyda Gonzalez-Almeyda, Ryan H. Cho, Kimngan Nguyenle, Erik Serrano, Briana Ondatje, Rebecca L. Benhaghnazar, John Yu, Clive N. Svendsen, Ravinder Abrol

Additional Authors: Romny Sanchez, Harry B. Gray, Zeev Gross

Funding: This research was supported by grants from the National Institutes of Health (NIH) [NCI R01 CA258204, R01 CA270324, and NCATS UL1 TR001881 core vouchers V002, V087, and V176 to L.M.K]; and the Department of Defense (DoD) [BCRP W81XWH-15-1-0604, W81XWH1910592 to L.M.K and R.A.]. F.A.V. was supported in part by a training grant from the National Institutes of Health [T32 HL134637]. B.O. and S.S. were supported by National Institutes of Health (NIH) UG3NS105703.

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