The R01 grant is the third such NIH award earned by Ostrow researcher and faculty member Dechen Lin, an accomplishment made all the more impressive given the extremely competitive funding environment.

HEAD AND NECK SQUAMOUS CELL CARCINOMAS are the seventh most prevalent form of cancer, but patient treatment responses can vary greatly. For many people, the treatment is as challenging as the disease itself – some patients experience face and neck immobility, while others can struggle to eat after chemotherapy or radiation therapy.

Now, a new National Institutes of Health grant will allow Professor Dechen Lin to investigate the role of a gene called KMT2C in the disease’s development. He is using tiny, three-dimensional tissue cultures grown in a lab from stem cells — known as human organoids — to study tumors in fine detail. This new five-year award will support his team’s efforts to understand this gene – and how to better predict who will benefit from therapies.

In a previous study, Lin’s group identified KMT2C, which is frequently mutated in head and neck cancer and plays a crucial role in controlling how DNA is packaged and which genes are turned on or off. Surprisingly, they found that this epigenetic regulator also helps the immune system’s ability to recognize and kill tumor cells.

The new R01 has two major aims. First, Lin’s team will continue to probe how removing KMT2C from precancerous lesions changes the behavior of tumor cells as well as the immune cells surrounding them, using organoids derived from patients seen in Ostrow’s new Oral Care PreCancer and Pain Clinic as well as in Keck’s otolaryngology department.

Second, they will test whether KMT2C mutations can serve as a biomarker to predict which patients are unlikely to respond to commonly used immune checkpoint blockade therapies. The researchers have identified an immune-related signaling route, the interferon pathway, that appears to be dampened when the gene is lost.

While immunotherapy has been successful in treating many cancers, for head and neck cancer, it’s effective for only about 25 to 30 percent of patients. It’s hard to know which people will succeed, Lin explains. “In the clinic, there’s very limited biomarkers to predict which patients will derive meaningful clinical benefit from immunotherapy,” he says. “With this grant, we are now looking to prove or disprove whether KMT2C can be utilized as a biomarker to predict immunotherapy response in the clinic.”

A Competitive Funding Environment

The work also builds on Lin’s earlier research using organoids – miniature, three-dimensional avatars of patients’ tumors grown from their own cells. These organoids allow the lab to study the very earliest stages of cancer formation in tissues of the oral cavity and oropharynx, the hotspots for head and neck cancer. Lin’s lab has worked to develop these models, which are personalized – something that animal models can never be, he says. “Now, we can generate more organoids from more patients or cover more diverse patients.”

The grant also reflects a broader shift at NIH toward funding human-based models that more accurately mirror patient biology, Lin noted. It comes in an era of intense competition: National Cancer Institute paylines hover around five to six percent, meaning only a handful of proposals in each cycle are funded.

Lin has received three R01 grants since he arrived at USC four years ago. “I’m very grateful, especially if we think about the current environment in terms of federal funding,” he says. “It’s very, very competitive. You have to do great research, write great proposals.”

For Lin, the new grant shows an expanding, interdisciplinary effort that brings together surgeons, oncologists, nurses, epigenetics experts and computational scientists across USC – from the lab bench to the clinic. “It takes a village to get this done,” he says. “This is really a big, diverse team. It’s never isolated work.”