Healthy cells, as part of their regular lifecycle, sustain damage to their DNA. To grow and thrive, cells maintain a DNA damage response network, composed of particular signaling pathways that work together to detect and repair damaged DNA. Compromising this damage response network would seem to put anyone, or any living thing, at risk. Yet Kelly R. Hume, Clinical Sciences, is pursuing evidence that partially inhibiting DNA damage responses could have significant benefits for some cancer patients.
Hume, a clinical veterinarian and veterinary medical oncologist, divides her time between leading a research lab, training students for clinical practice and bench research, and treating patients at the Cornell University Hospital for Animals. Hume studies signaling pathways that are characteristic across animal species, including humans.
DNA Damage Response Network and Chemotherapy
Repairing DNA is business as usual for any healthy cell, but cancer kicks the damage response network into overdrive. “As a cell becomes cancerous, which really means it grows and divides when it shouldn’t, all that growing causes more than normal DNA damage,” Hume explains. “For those cells to keep replicating, they have to tolerate the damage—by either not caring that something is a little out of order or upregulating their response-and-repair mechanisms.” Upregulating means devoting more and more molecular resources to the signaling pathways that support DNA damage responses.
Tumors that tolerate elevated DNA damage may get the benefit of a hyperactive DNA damage response network to sustain pathological growth. They may also gain even more: Chemotherapy kills cancer cells by damaging their DNA so extensively that they cannot recover. Hume began to suspect that cancer cells that upregulate response-and-repair mechanisms might be less susceptible to chemotherapy. Starting with biopsies from cat patients with newly diagnosed feline sarcoma, Hume’s lab tested the tissue samples for DNA damage. “We found some samples had a lot, some samples had a little.” They then tested the samples for sensitivity to the common chemotherapy drug carboplatin. Cell cultures grown from the samples with higher levels of damage proved to be less susceptible to carboplatin, offering preliminary confirmation of Hume’s hypothesis.
Hume isn’t drawing too many conclusions based on cell cultures alone, but she is looking forward to the next round of experiments. “The correlation between DNA damage levels and carboplatin sensitivity seems to be true in the lab. Is that true in a patient? There have been studies in people with breast cancer and lung cancer where that seems to be true. So then you would hopefully come up with a way to say, ‘Ok, if your levels of DNA damage are low, maybe it makes sense to include carboplatin as part of your treatment regimen; and if your sample levels are high, maybe that’s not the best option for you.’ But then we also use those cells to say, ‘Ok, now we know these cells are resistant. What can we do to try to make them sensitive to treatment?’”
Improving Cancer Drugs, Making Them Affordable for Pet Owners
An interest in making existing chemotherapy drugs more effective propels much of Hume’s research. “I am really excited by the data with the DNA damage expression and the correlation with carboplatin sensitivity,” Hume says. “Drug development takes a really long time, whereas the whole challenge of who benefits from a particular treatment and who wouldn't doesn’t require developing new drugs. It's important to develop tests aimed at understanding which patients will benefit from a drug. This way people don't waste time and money on therapies that don't work.”
“A lot of pet owners can’t afford cancer treatment, like traditional chemotherapies,” Hume adds. “One of my interests is finding affordable therapies.” Finding a new application for an already approved drug or a test that predicts which treatment will work best for a particular patient contributes to more cures at less cost.
“This might be an affordable way to make doxorubicin more effective, rather than developing a brand-new drug with the same mechanism.”
In another study, Hume’s lab found that salinomycin, an antiparasitic medication approved for use in poultry feed, increases the effectiveness of the common chemotherapy drug doxorubicin. It’s a promising result. “This might be an affordable way to make doxorubicin more effective, rather than developing a brand-new drug with the same mechanism,” explains Hume. “One of the reasons I had this interest in the salinomycin is it’s something that’s already available,” Hume says. “The next step is to figure out a safe dose of salinomycin.”
When Hume began veterinary school, she did not imagine that she would someday lead a research lab. “I became a veterinarian because I liked science and I liked animals. Then in vet school I really liked my oncology class.” After veterinary school, Hume won a competitive internship. After the internship, she elected to do a residency. At every step, Hume found herself drawn to cancer research. Her pursuit of lab experience, however, was always in the service of becoming a more effective clinician. “I was always going to go out into practice,” Hume says. Her efforts ultimately led to a research fellowship in the lab of Robert Weiss, Biomedical Sciences. Weiss introduced Hume to the DNA response-and-repair mechanisms that she studies today.
“I had just come out of my residency. Cornell was the only university that had a position available where I could get research experience and still be able to practice my specialty. I really appreciated the opportunity to do both of those things at the same time,” says Hume.
Hume’s research reflects a practical bent, an outgrowth of interacting with pet owners and seeing animal patients at the Cornell University Hospital for Animals on a regular basis. “The things I do in my research really have to do with what I’ve seen clinically,” Hume says.