Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide, with about 600,000 new cases each year, with 50,000 in the United States. It occurs most often in men in the 50s or 60s, though rates are increasing among younger individuals.
Typically, HNSCC arises from mutations in the body’s cells that occur during an individual’s lifetime. Risk factors include tobacco and alcohol, with HPV infection accounting for the rise in younger patients with the disease. Treatment can be traumatic, leading to reconstruction of portions of the oral cavity or facial features. And, only about half of affected individuals survive more than 5 years after diagnosis.
Yet help is on the way. The National Institutes of Health (NIH) has awarded a 4-year grant to the MD Anderson Cancer Center at the University of Texas to bioinformatically and functionally investigate genomic alterations as therapeutic targets for HNSCC. Jeffrey Myers, MD, PhD, will lead the research team. In this Q&A, he describes his team and its methodology.
Q: What sets the new line of research apart from previous theories?
A: We are using a team approach that bridges the spectrum of expertise from computational biology to tumor biology to high-throughput genomic screening to identify and validate potential targets for the treatment of oral cancers.
Q: Can you briefly summarize the methodology that will be used?
A: Specific aim 1.0 is to use computational approaches to discover genes, pathways, and drugs that regulate the growth and survival of HNSCC. Genomic analyses of HNSCC have identified many frequently mutated genes that are not targetable. In this aim, we will utilize computational tools based on evolutionary action to identify new candidate targets in HNSCC. Since this method is based on the impact of the mutations, not the frequency, it is able to identify cancer genes with a higher sensitivity and specificity than other methods. It will also be applied to groups of genes in pathways as another approach to identify previously undetected candidate targets and pathways that regulate tumor growth. This will be performed through 3 sub-aims:
- 1.1: Score deleterious mutations.
- 1.2: Identify cancer-associated genes.
- 1.3: Identify disease-causing pathways.
Specific aim 2.0 is to discover and confirm novel therapeutic targets for head and neck cancer in vivo. In this aim we will test more than 1,000 candidate drivers and targets for their ability to regulate growth or survival of HNSCC. In order to most accurately reflect human disease, all experiments will be performed in genomically characterized cell lines and patient derived xenografts (PDX) representing the spectrum of genomic alterations found in patients. The biological relevance of genes will be identified through an in vivo functional screen performed across a panel of cell and PDX lines containing diverse and clinically relevant genomic alterations. Validated targets will be further tested for their genotype dependence. Targets with known drug interactions will be tested in preclinical models. Additional candidate targets identified in aims 1 and 3 will be incorporated into a second in vivo screen. This aim will be carried out in 4 sub-aims:
- 2.1: Identify novel targets in HNSCC through an in vivo screen, phase I.
- 2.2: Determine genotype dependence of validated targets.
- 2.3: Preclinically test candidate druggable targets.
- 2.4: Identify additional novel targets in HNSCC through an in vivo screen, phase II.
Q: Who are the key personnel who will be involved in the research?
A: Olivier Lichtarge, MD, PhD, is leading the computational aspects of the study. He is the Cullen Foundation chair and director, CIBR Center for Computational and Integrative Biomedical Research, professor of molecular and human genetics departments of molecular and human genetics, pharmacology, and biochemistry and molecular biology.
Mitchell Frederick, PhD, is leading the integration of computational information and genomic screening lab and is the main project lead for the entire grant.
Tim Heffernan, PhD, is leading the genomic screening efforts. He is the associate senior scientific director for the Applied Cancer Science Institute.
Curtis Pickering, PhD, works closely with Dr. Frederick and is helping to oversee the integration of computational and genomic screening data and validation of these data in tumor models.
Q: Could you provide monetary totals for the first year of the grant and the subsequent years?
A: The direct costs are $720,000 per year for 4 years.
Q: Looking ahead, how could this research influence dental care?
A: It is anticipated that this approach will identify genes that are driving oral cancers and that this information will lead to more precise ways to select the best treatments for patients that will help them to live longer with the least amount of treatment-related morbidity.
Dr. Jeffrey N. Myers received his MD and PhD from the University of Pennsylvania School of Medicine. He completed his residency training in otolaryngology-head and neck surgery at the University of Pittsburgh. Subsequently, he completed fellowship training in head and neck surgical oncology at the University of Texas MD Anderson Cancer Center, where he has been on the faculty ever since. He leads a basic and translational research program, and his primary research interests are in the role of p53 mutation in oral cancer progression, metastasis, and response to treatment.