Making chemotherapy effective for transplant recipients

Balbo Lab

In addition to causing side effects such as vomiting or hair loss, chemotherapy is thought to play a significant role in how patients respond to blood and marrow transplantation, impacting everything from whether a transplant is accepted or rejected to cancer relapse. No one knows why some respond well to chemotherapy while others do not. But if Masonic Scholar and U environmental health sciences faculty member, Silvia Balbo, Ph.D., is right, the answer has a lot to do with our genes.

Silvia BalboWith Masonic support, Balbo is working to pinpoint how chemotherapy drugs interact with DNA to cause harm to genetically susceptible blood and marrow transplant recipients.

The end goal is simple, but powerful: to identify genetic markers that predict how well patients will respond to chemotherapy and, ultimately, the role it will play in the success of their transplant.

“Often with chemotherapy, we have a poor understanding of the outcomes of regimens we’re using and lack markers that will help us understand who will benefit from what therapy or dose,” says Balbo. “Our goal is to identify the DNA damage that occurs from transplant-related chemotherapy so that doctors can adjust and personalize chemotherapy drugs based on each patient’s profile.”

“Before getting a blood and marrow transplant to treat cancer, patients go through a seven-day regimen of chemotherapy that basically wipes out their immune system. Some react well, some don’t. Some have high toxicity, some don’t. Some have successful transplants, some don’t. We’re trying to define the DNA modifications produced by these drugs and their correlation with toxicity, side effects, and transplant outcomes.”

–Silvia Balbo, Ph.D., Masonic Scholar

Of mutations and medicine

To understand the extent of DNA damage caused by chemotherapy, Balbo and her team are using an innovative analytical approach called DNA adductomics.

Instead of the standard approach of zeroing in on one modification at a time, adductomics uses high-resolution mass spectrometry to reveal all DNA modifications caused by an exposure.

“Adductomics looks at all of the different modifications that are present in DNA after exposure to a particular chemical, drug, or toxin,” Balbo explains. “If we can figure out how these exposures interact with and alter DNA, we can use interventions that will prevent damage from occurring in the first place.”

Balbo and her team are currently working to recruit patients to follow during their chemotherapy “pretreatment” and monitor after their blood and marrow transplant. In the end, they hope to identify a set of biomarkers that doctors can use to predict how future transplant recipients will respond to chemotherapy so that they can customize therapeutic regimens to be more effective.

“If we could get a blood sample from a patient, expose it to a chemotherapy drug beforehand, and see the DNA modifications it causes for that patient before they receive chemotherapy, that would allow us to adjust the chemo so that it’s not as toxic and more successful,” Balbo explains.

While Balbo and her team have used adductomics to identify DNA damage caused by other exposures, such as alcohol or cigarettes, she is enthusiastic about the immediate impact their chemotherapy research could have on patients.

“Sometimes, when we use adductomics to look for modifications caused by alcohol or cigarettes, for example, exposure to these substances occurs in such low amounts that it’s harder to link DNA changes to them,” Balbo says. “But with chemotherapy, we have patients who are exposed to high doses of these drugs, so there’s a clearer effect on the DNA that we can readily detect with our technology.”

World-renowned technology

Through it all, an essential ingredient to Balbo’s success has been access to the cutting-edge technology offered through the Masonic Cancer Center, University of Minnesota.

“The center’s analytical biochemistry facility, which houses state-of-the-art high-resolution mass spectrometry instruments, provides opportunities you wouldn’t have anywhere else,” says Balbo. “If I had to think of where to go to do the work that I’m doing, there aren’t many places like this in the world.”

Balbo sees this phenomenon play out time and again with the postdoctoral and Ph.D. students she mentors who are planning their next career move.

“What they’re encountering is that they’re going places that are interested in their work, but these places are not able to offer the technology we have here,” Balbo reflects. Balbo herself holds a Ph.D. from the University of Turin in Italy and worked for several years at the International Agency for Cancer Research in Lyon, France. Were it not for the Masonic Cancer Center’s sophisticated analytical biochemistry facility, Minnesota would never have been on her radar.

“This facility is very special and a reference worldwide for the type of research we do on small molecules and DNA damage,” Balbo says. “It’s what brought me here and is definitely what keeps me here.”

The impact of your support

Another factor that is helping Balbo to thrive is donor support.

Over the years, funding from Minnesota Masonic Charities has been a driving force behind her research on DNA damage caused by environmental and lifestyle exposures. It has also enabled her to take her work in an exciting new direction with her new chemotherapy research.

“Nothing would have been possible without Masonic support,” Balbo explains. “I just couldn’t have started my own research. I got my start thanks to them.”

“The generosity of the Masons has really ignited my work. It has sparked so much momentum and has made research that I hope will ultimately save lives possible, doable, and meaningful.”

Unraveling alcohol’s effects

Six years ago, Silvia Balbo and her team made headlines when they used DNA adducts to show that alcohol induces DNA damage in the oral cavity, shedding new light on the connection between alcohol drinking and increased risk of head, neck, and esophageal cancer.

After giving 10 volunteers increasing doses of vodka once a week for three weeks, they found that DNA damage increased up to 100-fold in the participants’ oral cells within hours of each dose.

Today, Balbo and her team continue to seek answers to what specific aspects of alcohol lead to cancer, using adductomics to understand and map the different reactions it causes.

“Our goal is to eventually use this knowledge to create therapies or perhaps supplements that prevent alcohol from harming DNA in susceptible people,” says Balbo.

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