Grinnellians Pursue a Lung Cancer Cure

Charvann Bailey could not be found in the Noyce Science Center last year, but she hadn’t strayed from the vibrant community of Grinnell scientists that thrives there. Quite the opposite, in fact — the assistant professor of biology was only an hour away by car, on research sabbatical in the laboratory of Doug Spitz ’78 at the University of Iowa Carver College of Medicine.

Bailey considers herself a molecular biologist, while Spitz specializes in redox biology (studying electron gain and loss in biochemical processes), but their research interests converge when it comes to the treatment of aggressive, therapy-resistant cancers. The two joined forces through the University of Iowa’s FUTURE in Biomedicine Program, designed to open UI laboratories to professors from Iowa colleges without doctoral programs.

A Protein Link, a Research Pivot

Bailey has spent most of her career studying how a protein — enchantingly named SLUG — causes the resistance to chemotherapy that is exhibited by the most aggressive breast cancers. In recent years, however, studying SLUG has led her to a multitalented family of proteins linked not only to aggressive breast cancer but to lung cancer as well: the sirtuins. Sirtuins are signaling proteins that mediate chains of metabolic events within the cell.

“We know that a sirtuin protein is responsible for stabilizing the SLUG protein and causing aggressive breast cancers,” Bailey says. “But we’ve also recently learned that sirtuins are highly expressed in lung cancer cells, too. It’s an interesting connection between these two kinds of cancer.” This connection — and the mysterious role of sirtuins in lung cancer — brought Bailey to the Spitz laboratory and pushed sirtuin proteins to the forefront of her sabbatical research.

At the University of Iowa, Bailey and Spitz set themselves the task of piecing together the involvement of sirtuins in aggressive lung cancer. Could targeting and inhibiting the proteins help treat seemingly untreatable cancers?

Bailey began with a simple test. She dosed lung cancer cells with sirtinol — an inhibitor of several sirtuin proteins — to see whether the drug stopped cells from cloning. It did. She spent the rest of her sabbatical figuring out why.

Decoding a Toxic Cellular Relationship

The Spitz laboratory explores how high levels of molecules with extra electrons (known as free radicals) can wreak havoc within cells and how treatments might target cancer cells by inducing this “oxidative stress.” So, when Bailey proved that sirtinol could stop replication of aggressive lung cancer cells, the researchers’ immediate hunch was that sirtinol acted through some oxidative stress pathway.

Specifically, Bailey hypothesizes that sirtinol interferes with the systems that cancer cells have in place to decompose hydrogen peroxide. Undecomposed, hydrogen peroxide within cells will form harmful free radicals and damage the cells.

Bailey designed experiments to prove that sirtinol’s inhibition of sirtuins affects catalase, the enzyme that kickstarts the decomposition of hydrogen peroxide. When she treated lung cancer cells with sirtinol, catalase enzymes were less effective and toxic hydrogen peroxide accumulated.

Causing oxidative stress seemed to be one piece of the sirtinol puzzle, but it didn’t seem to fully account for sirtinol’s ability to stunt cell cloning. Bailey explains, “We know that there are likely several pathways by which sirtinol works against cancer cells, so we had to separately decode these individual pathways in hopes of achieving the bigger picture.” Essentially, she and Spitz had to look beyond oxidative stress.

Ore to the Story

Bailey says that there’s another way that sirtinol might be devastating cancer cells: iron burglary.

Recent publications had suggested that the sirtinol molecule can bind iron inside cells. Were this so, Bailey reasoned, sirtinol would end up depleting cancer cells’ iron stores and effectively starving them of the essential nutrient. Iron metabolism seemed like a pathway worth exploring.

Alongside biology student Koffi Amegble ’23, Bailey designed experiments to probe the interplay between sirtinol and cancer cell iron metabolism. Over the summer of 2022, the two proved that sirtinol snatches up free iron in aggressive lung cancer cells, leading to the dysregulation of critical proteins in the cells’ iron metabolism. Amegble presented their findings in November at the Mid-States Consortium in Biological Sciences and Psychology, hosted by the University of Chicago.

A Molecule with Promise

Though Bailey returned to campus to teach last fall, she and Amegble have continued their studies of sirtinol and its iron-related mechanisms. The two are currently compiling their findings in a paper that they plan to submit for publication this spring. They’ve also begun testing sirtinol’s efficacy in concert with other types of cancer therapies, probing the molecule’s fitness for clinical use.

"Down the line," Bailey says, "the studies we're conducting could be the proof of concept for a therapeutic trial. That's really the long-term goal we're working toward."

Just a few weeks ago, the Spitz laboratory collected data that catapulted them closer to that goal: They confirmed that sirtinol preferentially targets cancer cells. If sirtinol is to be used therapeutically, this preference is critical. It means that the drug can target and kill cancerous cells while leaving healthy cells undisturbed.

Though plenty of research stands between sirtinol and a clinical trial, Charvann Bailey looks to the future optimistically. In just one year, she identified the molecule as a candidate therapy for one of the most notoriously difficult-to-treat cancers and made massive strides toward explaining its potency. Asked about her sabbatical, Bailey laughs and says, “It was a busy year.”

This is, of course, an understatement.