image: Antonio Jimeno, MD, PhD, and Tin Tin Su, PhD view more
Credit: Antonio Jimeno, MD, PhD, and Tin Tin Su, PhD
Two University of Colorado Cancer Center researchers have received a five-year R01 Award for $497,893 per yearfrom the National Institutes of Health (NIH) tostudy a potential new drug treatment for salivary gland cancer.Theaward is part of an inter-campus collaboration between Antonio Jimeno, MD, PhD, co-leader of the Developmental Therapeutics Program, and Tin Tin Su, PhD, co-leader of the Molecular and Cellular Oncology Program.
An orphan disease
Salivary gland cancer(SGC)is a rare disease for which there are currently noapprovedtargetedtherapies. According to Jimeno,this isdueprimarilyto the fact thatSGCisahypomutateddisease,meaning it hasvery few oncogenic(cancer-causing)geneticmutations. Thismakesitchallengingto treatwith traditionaldrugtherapiesthat target proteins bearing activating mutations.
“For example, the successes we’ve seen in lung,colorectal,andbreast cancer, where specific mutationsareselected for aspecificdrug, havenot beenfruitfulin treating salivary gland cancer,” says Jimeno, thedirector of the Head and Neck Cancer Clinical Research Program at theUniversity of Colorado School of Medicine.
“In general,hypomutatedcancers also developfewerneoantigens (proteins that form on cancer cells when certain mutations occur in tumor DNA), making them less visible to the immune system and harder totarget with immunotherapy,” Jimeno says. “Cancers withhigh mutation ratescanoftenbe managed with immunotherapy because thosecancercellsare moreabnormal,making it easier for immune cells to find them.”
BecauseSGCis so rare, it has historicallybeendifficultto study in the lab.With only about 4,000 cases per year in the U.S.,SGCis consideredanorphan disease.In the United States, an orphandiseaseis usually defined as a disease or condition that affects fewerthan 200,000 people.
“Since it’s a rare disease, there are only a handful ofsalivary gland cancercell lines available, and they're not extremely easy to work with,” Jimeno says. “So,that has precluded meaningful advances in the past.”
To remedy this,Jimeno’slabundertook thetaskof generatingpatient-derived xenografts (PDXs).Essentially,whenaSGCpatient undergoesa resectionto removeatumor,Jimeno’s team receives a sample of the tumor tissue, which is thenprocessed andimplanted intomice. After a few weeks or months,tumors grow on the mice, creating aPDXmodel.From there, the teamcanderive cell lines, which they characterize molecularly using a variety of Cancer Center Shared Resources, including the Functional Genomics Shared Resource and the Flow Cytometry Shared Resource.This gives researchers more avenuesto study both the biology of the cancer and how it responds to treatments.
"There are things that you can dowithcell lines that you cannot dowith tumors implanted onanimals,and vice versa,” Jimeno explains. “But if you have both, youcando a very comprehensive set of experiments. For example,the cell lines are criticalfor studyingmutations and fusion proteins,buttheanimal models are preferablefor therapeutic experimentation to see if a drugactually shrinkstumors.”
Fusion proteins: Salivary gland cancer’sAchillesheel
Finally equipped withamplesalivarygland cancerPDX models andcelllines, Jimeno andSuhavebeen able to advance the study ofthe diseaseat both the cellular and tumor level.
“It's a true collaboration between basic research scientists like myself and clinicians and physician scientists likeDr. Jimeno,” saysSu, a professor of Molecular, Cellular, and Developmental biology at the University of Colorado at Boulder.
And they’vefound apotential target forSGCtreatment:fusion proteins.
“SVC112 selectively kills cancer cells at a higher rate than normal cells ... It's like finding the Achilles’ heel in a cancer cell.” - Antonio Jimeno, MD, PhD
Fusion proteinsare created by joining parts oftwo previously independent genes, causingrearrangements of the DNAin the process.AndinSGC,these fusion proteinsand the resulting DNA changesseem todrivetumor formation.
Su’sCU Boulderlab andthe bio-tech company she co-founded,SuviCa,havecreatedand patentedafamily ofsyntheticcompoundsthatselectivelyinhibitthe production of fusionproteinsin cancer cells.Importantly, the drugcandidate, SCV112, appears toprimarilyinhibitprotein production in cancer cells— notinhealthy cells.
“SVC112selectively killscancer cells at a higher rate thannormal cells, because itinhibitsproteins that normal cells don't regularly use butthatcancer cells need to survive,” Jimeno says. “It'slikefinding the Achilles’heel inacancer cell.”
Suis especially excited aboutSVC112’s potential to prevent SGCfrom recurring.
“With currenttreatments, such as chemotherapy, it often looks like it worked,butalotof patients willrelapsea few years later,” she says. “We want to be able to target those stealth cellsthat get left behind and regrow the tumors. That is one of the things that we're excited about with this drug candidate— it seems to be very good at destroying those tumor-initiatingand tumor-regrowingcells.”
Research could lead tofutureclinicaltrials
Jimeno andSuhave three main goals they hope to accomplish with the new funding from the NIH grant.
First, theywillinvestigatethe role offusion proteinsindrivingSGCusing cell lines.
Second,they willexplorehow the newdrugcandidate SVC112impactsthesefusion proteinsto slow or haltSGC.
Finally,they willdeploySVC112 in animal models(PDXs)ofSGCto determinewhether the drug effectively shrinks tumors.“At the end of the day, I'm an oncologist,” Jimeno says. “I like to see tumorsshrink ordisappear.”
If theproject is successful,Jimeno says the next step would beto moveSVC112into clinical trials for patients.“Right now, there are no therapies approved for salivary gland cancer,” he says. “That is a great unmet need for our patients. So, finding a treatment — that's the overarching goal.”
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