First-of-Its-Kind Drug Shrunk Oral Tumors in Pet Cats

Oral cancer is often a death sentence in cats. Sick cats excel at hiding their symptoms, so the cancer is typically diagnosed at an advanced, untreatable stage.

“Most of the time these cats come in, I have to give the owners bad news that their cat likely only has weeks to live,” said Katherine Skorupski, a veterinary oncologist at the University of California, Davis. “Our focus tends to be end-of-life care, so we’ve always been eager to look at experimental options.”

In a recent clinical trial involving 20 cats with oral cancer, Skorupski collaborated with physician scientist Jennifer Grandis and biochemist Daniel Johnson at the University of California, San Francisco to evaluate the safety of a drug targeting Signal Transducer and Activator of Transcription 3 (STAT3), a notoriously hard-to-hit protein.¹ They showed that the molecule was non-toxic even at relatively high doses. It also halted disease progression and shrunk tumors in some cats. Their findings, published in Cancer Cell, may pave the way for new cancer treatments for cats.

“There are not a lot of comparable studies that have been done on [cat oral cancers],” said Douglas Thamm, a veterinary oncologist at Colorado State University who was not involved in the study. “The fact that there was any hint of biological activity observed in the study is very, very encouraging.”

Many researchers have observed that STAT3 is often hyperactivated in both cat and human cancers.^2,3 However, “STATs, and transcription factors as a whole group, have been a complete nightmare,” said Matthias Ernst, a cancer biologist at La Trobe University who was not involved in the study. Transcription factors lack the pocket-like structure where small molecules can bind, so most existing drugs that target them suffer from off-target toxicities.

Over two decades ago, Grandis and Johnson designed a “decoy” oligonucleotide molecule that mimics STAT3’s target DNA sequence.⁴ Since STAT3’s function depends on its binding to this target sequence, the 15-basepair double-stranded DNA decoy inhibits the protein’s activity by interfering with this interaction. At the same time, it helps researchers get around the issue with off-target specificities. "They don't talk about specificity in the paper, but 15 nucleotides usually should give you sufficient specificity," Ernst said.

To prevent the molecule from being rapidly degraded or eliminated from the body, the researchers cyclized the double-stranded DNA. In 2012, Grandis and Johnson showed that cyclic STAT3 decoy (CS3D) was stable in mouse serum and could halt STAT3 activity and tumor growth in cell lines, mice xenografts, and human tumors.⁵

The inspiration to work with cats came from Grandis’s sister, who is a veterinarian. “My sister has always said to me, ‘Jenny, I see one or two cats a month in my private practice that have oral cancer, and they all die. Can’t you help these cats?’,” Grandis shared. Her sister’s request eventually prompted Grandis to reach out to Skorupski, whose team enthusiastically accepted Grandis's invitation to collaborate.

Over the course of the month-long trial, the researchers administered six increasing doses of CS3D intravenously to the 20 participating cats. The treatment halted disease progression in five cats and considerably shrunk tumors in two—it even extended one cat’s life by nearly a year. The researchers found no visible toxicities, except for mild anemia. However, Skorupski noted that anemia is common in cats with cancer, and the effect didn’t seem to depend on CS3D dose.

The DNA target sequence that CS3D mimics is 100 percent identical in humans and cats, so the researchers hope that their findings may someday also help human patients. There are also other similarities between cat and human cancers, such as how these cancers spontaneously arise, which can’t be recapitulated using mouse models.

“I have never read a paper using pet animals, particularly cats, as a preclinical model,” Ernst said. “I think that is a very, very nice aspect of the paper.”

Thamm added, “This model potentially has a higher fidelity than what you can get with mice. Murine models are important, but I think there’s a different kind of information that can be gained from these spontaneous tumors in companion animals.”

The researchers are currently working with a small biotech company to plan further clinical trials in cats. Johnson also hopes that cyclic decoy molecules could target other transcription factors in other diseases. “The technology is likely a good platform for inhibiting other transcription factors—think about MYC and NFkB—which people have been trying to hit for many, many years, largely unsuccessfully,” he said.

Ernst said, “I think this is a space to watch.”