Head and neck squamous cell carcinoma (HNSCC) is approximately the seventh most common cancer in humans with an estimated 900,000 new cases globally.  

As a surgeon, Jennifer Grandis, MD, a physician scientist and professor at the University of California, San Francisco (UCSF), recalls how her operations to treat HNSCC were often inadequate to extend the life of her patients. Rather, the consequences of surgeries were frequently severe, leading to the loss of the ability to speak and breathe.  

2,500 miles away, Grandis’s sister, Joanna Rubin, VMD, founder and owner of the Bridgeville Animal Hospital located south of Pittsburgh, saw a similar story. Rubin’s feline patients commonly entered the clinic with malignant oral tumors that were difficult to treat due to an invasive nature that spreads to the jawbone. In contrast to dogs, who have surgical treatment options, the cat anatomy is too small for operations. The cancer diagnosis is often fatal with a prognosis of only a few weeks.

“My sister would say ‘you need to help my cats. I see one or two cats a month with this horrible oral cancer and they all die. There’s no treatment,’” Grandis recalled in an interview with GEN.  

Grandis currently leads a research team that investigates signal transduction in HNSCC development and progression to identify key pathways for therapeutic benefit. In a new study published in Cancer Cell titled, “Safety and efficacy of a STAT3- targeted cyclic oligonucleotide: From murine models to a phase I clinical trial in pet cats with oral cancer,” Grandis and colleagues from UCSF and University of California Davis School of Veterinary Medicine have now developed a novel decoy mechanism that targets STAT3, a transcription factor and historically elusive therapeutic target involved in almost all cancer hallmark features, including tumor metastasis, immunosuppression, cancer drug resistance, and more. 

The new therapy has shown promise mitigating oral cancer in a cat clinical trial, offering a translational avenue for human HNSCC. Grandis, along with Daniel Johnson, PhD, professor in the Department of Otolaryngology at UCSF, are co-corresponding authors of the study.  

“I went to medical school to help people. As Dr. Johnson and I were bringing this into the clinic, it occurred to us that the clinic could be companion animals,” Grandis told GEN. “This particular story dovetails with what moves me, which is cats are patients too.” 

More than safe 

The study showed that the cyclic STAT3 decoy (CS3D) treatment was non-toxic even at the highest dose (10 mg/kg) tested in the study. Other than mild anemia, none of the cats in the trial developed side effects that were attributable to the therapy. 

Of the 20 cats that were enrolled, seven exhibited either a partial response or stable disease during the study period. Cats who responded to the treatment showed improved immune parameters, including elevated PD-1 expression in the tumors compared with non-responders. Among the responders, the average survival post-treatment was 161 days, a significant improvement on the standard four to eight week prognosis.

“The primary objective of a Phase I trial is safety. We were pretty sure based on our preclinical evidence in rodent models that this was going to be an exceptionally safe molecule,” said Grandis. “We were thrilled that a third of the animals also had a persuasive disease control rate.” 

Katherine Skorupski, DVM, professor of surgical and radiological sciences at UC Davis and co-author on the study, highlighted that two cats in the trial experienced remarkable tumor reduction, with one cat’s tumor shrinking to a state of slight ulceration followed by significant healing over the following weeks. 

“It was amazing to see the cats feeling better, being more active and eating,” Skorupski told GEN. “Cats are orally fixated creatures. They groom themselves and don’t do well with dental disease. Seeing their comfort improve was the best part for me as a clinician.”

One of the participants in the trial, Jak, a nine-year-old black domestic shorthair, was given only six to eight weeks to live upon his cancer diagnosis. Jak went for weekly treatments for one month and ultimately lived more than eight months after his diagnosis. 

“It was meaningful to us because he was here in our lives,” said Tina Thomas, Jak’s owner, in a public release. “During that time, my son finished college and my daughter finished her master’s program. Jak got to spend one more Christmas with us, and he loved our Christmas tree. He was worth every bit of the effort.” 

Combat resistance 

STAT3 has long been considered a challenging cancer drug target due to its hard-to-access intracellular location and lack of enzymatic activity. Currently, no STAT3 inhibitors have been approved by the US Food and Drug Administration (FDA). 

While a common STAT3 inhibition strategy is to target upstream kinases, these inhibitors have often been ephemeral due to rising drug resistance. In contrast, the cyclic STAT3 decoy (CS3D) competitively inhibits STAT3 binding to target gene promoters, offering a novel mechanism that may bypass the resistance issue.  

“There’s always a danger that the target protein is going to mutate, and the drug no longer binds,” explained Johnson in an interview with GEN. In contrast, STAT3 mutations that disrupt CS3D binding would also prevent STAT3 interaction with genomic promoter elements, thereby maintaining STAT3 inhibition for therapeutic effect.  

As STAT3 is hyperactive in the majority of human cancers, including solid tumors and hematologic malignancies, CS3D has the potential to benefit an exceptionally large patient population. The new therapeutic mechanism can also provide a platform approach for other transcription factors implicated in cancer, such as Myc, c-Jun, and NFκB. 

Grandis is hopeful that further optimization of the molecule and the dosing regimen will allow CS3D to move forward in the drug approval process for humans. Future steps for human translation will investigate CS3D in combination with other treatment options, such as cetuximab, an FDA-approved monoclonal antibody that treats HSNCC by blocking epidermal growth factor receptor. In addition, Bluedot Bio, a cancer therapy start-up, has licensed the patent for the CS3D technology to pursue the development of an oral cancer drug for cats.