April is Oral, Head and Neck Cancer Awareness Month, the perfect time to shine a spotlight on the innovative research happening at the Head and Neck Cancer Lab in the Department of Otolaryngology – Head and Neck Surgery at the University of California, San Francisco (UCSF OHNS), part of the Helen Diller Family Comprehensive Cancer Center. The lab is dedicated to increasing clinicians' understanding of head and neck squamous cell carcinoma (HNSCC) to develop new treatment and prevention approaches.
The lab is led by three principal investigators who also serve as members of the UCSF OHNS faculty - Jennifer Grandis, MD, Patrick Ha, MD and Daniel Johnson, PhD and a research team made up of junior research specialists, research specialists, assistant researchers, medical students and post-doctoral and visiting scholars. Here's a summary of a few of their ongoing research efforts:
Molecular factors and pathways regulating adenoid cystic carcinoma
Throughout his career, Dr. Ha has been involved in salivary gland cancer research, including a current focus on unique gene fusions found within adenoid cystic carcinoma (ACC). "ACC is a rare form of cancer in the head and neck - there are about 1,200 new cases diagnosed yearly in the U.S.," he says. "Current treatment involves surgery and radiation therapy but metastases is common (nearly 50% of cases). The problem is twofold. First, metastases can remain asymptomatic, and their contributing factors are not well understood. Second, there are no approved chemotherapeutic or targeted agents available to treat any stage of this disease."
The lab's research focuses on the identification of molecular factors and pathway/mechanisms, and their role in ACC tumor progression, as it will lead to the development of effective treatment strategies. Projects include the investigation to understand the unique alternative splicing events that occur in ACC and their contribution to ACC tumorigenesis, as well as testing promising novel compounds in an effort to bring new treatments to clinical trials.
Targeting STAT3 in Tumor and Immune Cells with a Novel and Innovative Inhibitor
"Our lab has played a leading role in identifying STAT3 transcription factor as a promising therapeutic target in HNSCC," says Dr. Johnson. STAT3 is hyperactivated in a majority of HNSCCs, as well as other solid tumor malignancies, where it promotes tumor growth, disease progression, and poor prognosis.
"To combat the effects of STAT3 hyperactivation, Dr. Grandis and I co-invented a highly novel decoy oligonucleotide inhibitor for this previously undruggable oncogene," says Dr. Johnson. Current efforts are focused on moving the STAT3 decoy to clinical evaluation in patients with HNSCC.
Therapeutic Implications of PI3K Pathway Activation in HNSCC
"In our lab, we've been at the forefront of determining the genomic landscape of head and neck cancer, and we seek to leverage this information, along with access to patient specimens and preclinical models, to develop innovative therapeutic approaches," says Dr. Grandis.
One of the research projects determined that PIK3CA, the gene encoding the PI3K catalytic subunit, is mutated or amplified in 35% of head and neck squamous cell carcinomas (HNSCCs), leading to activation of the PI3K signaling pathway and overexpression of COX2 enzyme. A proposed clinical trial could determine whether aspirin use improves overall survival in HNSCC patients with genetic alterations that lead to activation of the PI3K signaling pathway. Results from this trial may lead to dramatic improvements in survival outcomes for a large subset of patients.
"Collectively, these investigations into PIK3CA will facilitate the design of effective precision medicine strategies based on the mutational profile of the patient's tumor," says Dr. Grandis.
The Role of Caspase-8 Mutations in HNSCC
Mutations in caspase-8 protease, which occur frequently in HNSCC tumors, contribute to disease progression by abrogating cell death mediated by death ligands such as TRAIL and TNF.
"Our lab is investigating the impact of these mutations on caspase-8 function and their role in the development and progression of HNSCC," says Dr. Johnson. The impact of caspase-8 mutations on tumor-infiltrating immune cells and the tumor microenvironment is of particular interest.
You may also view a list of selected publications from the lab here.
