CWRU researcher to customize tobacco mosaic virus to treat human cancers

A Case Western Reserve University researcher has been awarded more than $3 million in federal and foundation grants to turn common plant viruses into cancer sleuths and search-and-destroy emissaries.

Nicole Steinmetz, an assistant professor of biomedical engineering, will customize tobacco mosaic virus to distinguish between indolent and aggressive prostate cancers, and potato virus X to deliver a pair of treatments inside triple-negative breast cancer tumors.

The National Institutes of Health's National Institute of Biomedical Imaging and Bioengineering (NBIB) and National Cancer Institute (NCI), and the American Cancer Society are providing the funding.

Prognostics

Steinmetz will target two potential biomarkers of aggressive prostate cancers.

"The overall problem is, as men age, they are at increased risk for prostate tumor development," Steinmetz said. "They may not have to be treated if the tumor is benign, but the current PSA (prostate-specific antigen) test--a blood test--is poor at telling slow-growing from aggressive cancers."

Her lab has already developed a self-assembling contrast agent to be used in magnetic resonance imaging (MRI) scans. The new agent includes a large payload of chelated gadolinium that has the potential to increase the visibility of molecular targets 10,000 times over current agents.

With a $2 million grant from the NCI, Steinmetz's lab will focus on detecting and monitoring the cell membrane protein tetraspanin CD151 over the next five years.

Co-investigator John Lewis, associate professor of oncology at the University of Alberta, found that patients with increased levels of the "integrin-free" CD151 in their prostates had significantly increased risk for metastasis--the most deadly aspect of prostate cancer.

Using a $275,000 grant from the NBIB, Steinmetz will target epidermal growth-factor like domain 7 (EGFL7), a protein coding gene. EGFL7 is expressed in the lining of prostate blood vessels that are actively growing, which is the case in aggressive prostate cancers.

The contrast agent will assemble inside hollowed-out protein shells of tobacco mosaic virus. The lab will customize the outside surface chemistry to seek and link to CD151 or EGFL7.

Injected into the bloodstream, the elongated shape of the virus shells allow them to evade the body's immune system and, by tumbling along the edges of the blood flow, more easily come in contact with and attach to the targets.

If an MRI shows CD151 or EGFL7 is present, the prostate cancer is considered aggressive and would require monitoring and treatment. If not found, no treatment is needed.

Because the contrast agent is packaged inside a protein, the researchers believe the body will recognize it as protein and quickly remove it from circulation, limiting tissue exposure to toxic gadolinium.

The work builds on long-term collaboration between Steinmetz and Lewis, who have developed several virus-based sensors targeting molecular zip codes --unique receptors in blood vessels and cancer cells of prostate tumors.

Other collaborators include Xin Yu, professor of biomedical engineering at Case Western Reserve and MRI physicist on the project. Sanjay Gupta, professor of urology, and James M. Anderson, professor of pathology, at the Case Western Reserve School of Medicine, will assess the safety and potential toxicity of the CD151 package.

Drug delivery

The American Cancer Society awarded Steinmetz $792,000 to produce a new chemotherapy delivery system to combat triple-negative breast cancer, one of the most aggressive forms of breast cancer.

Standard therapies targeting human epidermal growth factor receptor 2 and steroid receptors fail to work in Triple-negative breast cancer.

Steinmetz's lab spent several years developing filamentous potato virus X particles to carry medicines deep into tumor tissue.

"We want the drugs distributed throughout the tumor to produce a greater therapeutic effect," she said.

The flexible filaments are designed to use the leaky surface of tumor blood vessels as a doorway to slip into the tumor.

Once inside, the filaments are expected to migrate through the intercellular spaces, where the virus particles would deliver doxorubicin, which slows or stops cancer cell growth, and tumor necrosis factor-related apoptosis-inducing ligand, which turns on the cancer cell's machinery to trigger its own death.