Two University of Colorado Cancer Center researchers have received a five-year R01 Award for $497,893 per year from the National Institutes of Health (NIH) to study a potential new drug treatment for salivary gland cancer. The award 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 no approved targeted therapies. According to Jimeno, this is due primarily to the fact that SGC is a hypomutated disease, meaning it has very few oncogenic (cancer-causing) genetic mutations. This makes it challenging to treat with traditional drug therapies that target proteins bearing activating mutations.
“For example, the successes we’ve seen in lung, colorectal, and breast cancer, where specific mutations are selected for a specific drug, have not been fruitful in treating salivary gland cancer,” says Jimeno, the director of the Head and Neck Cancer Clinical Research Program at the University of Colorado School of Medicine.
“In general, hypomutated cancers also develop fewer neoantigens (proteins that form on cancer cells when certain mutations occur in tumor DNA), making them less visible to the immune system and harder to target with immunotherapy,” Jimeno says. “Cancers with high mutation rates can often be managed with immunotherapy because those cancer cells are more abnormal, making it easier for immune cells to find them.”
Because SGC is so rare, it has historically been difficult to study in the lab. With only about 4,000 cases per year in the U.S., SGC is considered an orphan disease. In the United States, an orphan disease is usually defined as a disease or condition that affects fewer than 200,000 people.
“Since it’s a rare disease, there are only a handful of salivary gland cancer cell 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’s lab undertook the task of generating patient-derived xenografts (PDXs). Essentially, when a SGC patient undergoes a resection to remove a tumor, Jimeno’s team receives a sample of the tumor tissue, which is then processed and implanted into mice. After a few weeks or months, tumors grow on the mice, creating a PDX model. From there, the team can derive 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 avenues to study both the biology of the cancer and how it responds to treatments.
"There are things that you can do with cell lines that you cannot do with tumors implanted on animals, and vice versa,” Jimeno explains. “But if you have both, you can do a very comprehensive set of experiments. For example, the cell lines are critical for studying mutations and fusion proteins, but the animal models are preferable for therapeutic experimentation to see if a drug actually shrinks tumors.”
Fusion proteins: Salivary gland cancer’s Achilles heel
Finally equipped with ample salivary gland cancer PDX models and cell lines, Jimeno and Su have been able to advance the study of the disease at both the cellular and tumor level.
“It's a true collaboration between basic research scientists like myself and clinicians and physician scientists like Dr. Jimeno,” says Su, a professor of Molecular, Cellular, and Developmental biology at the University of Colorado at Boulder.
And they’ve found a potential target for SGC treatment: 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 proteins are created by joining parts of two previously independent genes, causing rearrangements of the DNA in the process. And in SGC, these fusion proteins and the resulting DNA changes seem to drive tumor formation.
Su’s CU Boulder lab and the bio-tech company she co-founded, SuviCa, have created and patented a family of synthetic compounds that selectively inhibit the production of fusion proteins in cancer cells. Importantly, the drug candidate, SCV112, appears to primarily inhibit protein production in cancer cells — not in healthy cells.
“SVC112 selectively kills cancer cells at a higher rate than normal cells, because it inhibits proteins that normal cells don't regularly use but that cancer cells need to survive,” Jimeno says. “It's like finding the Achilles’ heel in a cancer cell.”
Su is especially excited about SVC112’s potential to prevent SGC from recurring.
“With current treatments, such as chemotherapy, it often looks like it worked, but a lot of patients will relapse a few years later,” she says. “We want to be able to target those stealth cells that 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-initiating and tumor-regrowing cells.”
Research could lead to future clinical trials
Jimeno and Su have three main goals they hope to accomplish with the new funding from the NIH grant.
First, they will investigate the role of fusion proteins in driving SGC using cell lines.
Second, they will explore how the new drug candidate SVC112 impacts these fusion proteins to slow or halt SGC.
Finally, they will deploy SVC112 in animal models (PDXs) of SGC to determine whether the drug effectively shrinks tumors. “At the end of the day, I'm an oncologist,” Jimeno says. “I like to see tumors shrink or disappear.”
If the project is successful, Jimeno says the next step would be to move SVC112 into 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.”