Analyzing the genetic drivers of head and neck cancers

Analyzing the genetic drivers of head and neck cancers

Newswise — Head and neck cancer, which kills more than 400,000 people worldwide each year, has multiple causes. Human papillomavirus (HPV), a sexually transmitted infection, is one, but the most common and deadliest subtype are HPV-negative head and neck cancers, which account for 3% of all tumors cancers in the United States and 15,000 deaths per year.

“Typically, head and neck cancers start in the squamous cells that line the mucous surfaces, such as inside the mouth and throat and there are multiple treatment options including surgery, radiation therapy and chemotherapy,” said Ezra Cohen, MD, co-director of the Gleiberman Head and Neck Cancer Center at UC San Diego Health’s Moores Cancer Center.

“But these cancers are complex and no treatment works for every patient every time, which is why immune checkpoint inhibitors have been developed, which use antibodies to make tumor cells visible to a patient’s immune system. .”

Immune checkpoint therapy (ICT) first emerged in the 1990s and has advanced considerably in recent years, but drug resistance in head and neck cancer remains widespread, poorly understood and largely unidentified by current biomarker testing, Cohen said.

Currently available PD-1 (a protein) immune checkpoint antibody therapy approved by the Food and Drug Administration produces long-lasting responses in 15% of patients with head and neck squamous cell cancer. The remaining 85% receive no benefit and may, in fact, experience serious immune system-related adverse effects.

Like other types of head and neck cancer, the HPV negative subtype has multiple risk factors, such as tobacco and alcohol consumption, but the primary cause appears to be genetic alterations in the number of copies.

In a new study, published in the November 14, 2022 issue of PNASCohen, along with colleagues at Moores Cancer Center, UC San Diego School of Medicine, and elsewhere, are broadening and deepening the understanding of how genetic aberrations fuel HPV-negative head and neck cancers and, potentially , pave the way for refinement and improvement of immune checkpoint inhibitors for HPV-negative head and neck cancers.

In research published last year, the same team of scientists laid the groundwork, becoming the first to discover the impact of losing one copy of a genetic region on the short p arm of chromosome 9 in causing the Immune evasion and ICT resistance of HPV-negative head and neck cancer.

But the 2021 findings have raised new questions about whether the genetic abnormalities could involve losses at more than one locus on chromosome 9p. The new work provides answers, based on multi-omics immunogenetic evidence from analyzes of every band at every locus, and every gene in every band in four different patient cohorts.

“We found that it is not only the 9p21 locus on chromosome 9p that is involved, but also the 9p24 locus, which may be even more important in resistance to immune checkpoint therapy; and surprisingly, we found that gains in these genetic regions, at least in the case of HPV-negative head and neck squamous cell carcinoma, were associated with a survival advantage of TICs,” said the co-lead author of the study and corresponding co-author Scott Lippman, MD, Distinguished Chugai Professor and Director of Moores Cancer Center.

The researchers found that median survival rates were three times higher when treating 9p gain cases, especially tumors with 9p24.1 band expression above the 60th percentile compared to chemotherapy (but below the threshold transcript). suggest that these 9p-related TIC findings may be relevant to squamous cell cancers, in which there are 9p24.1 gain/immune response associations.

These 9p24.1/immuno-oncology alteration findings reveal genetically defined TIC sensitivity and resistance in HPV-negative squamous tumors, addressing a major unmet medical need for precision therapy for these patients. They identify likely mechanisms of response and resistance to ICTs that point to treatment options that are more likely to be effective.

This finding could have a profound impact on the science and practice of immuno-oncology, Lippman said, revealing the basis and pattern of recurrent chromosomal alterations as oncogenic factors and key determinants of the immune phenotype, and identifying a new ICT resistance mechanism leading to a new standard diagnostic biomarker test.

“This work progressively defines the genetic basis for responsiveness to one of the most widely used forms of oncology therapeutics,” said co-author Webster K. Cavenee, PhD, emeritus professor emeritus at UC School of Medicine. San Diego. “The ability to identify these distinct groups of patients can be expected to have significant clinical impact for them.”

Co-authors include: Xin Zhao, Joy J. Bianchi and co-lead author Teresa Davoli; J. Silvio Gutkind and Ludmil B. Alexandrov, both at UC San Diego; William N. William Jr, University of Texas and Hospital BP, Brazil; and Jim P. Abraham, Daniel Magee, and David B. Spetzler, all at Caris Life Sciences, Texas.

Funding for this research came, in part, from Instituto Cura; Cancer Research UK Grand Challenge, Mark Foundation for Cancer Research (C5470/A27144), the National Institutes of Health (grants R00 CA212621, R37 CA248631, R01DE026644, P01 CA106451, P50 CA097007 and P30 CA023100); an MRA Young Investigator Award; the Packard Fellowship for Science and Engineering; the National Foundation for Cancer Research; and Stand Up To Cancer–Lustgarten Foundation Pancreatic Cancer Interception Dream Team Translational Cancer Research (grant SU2C-AACR-DT-25-17).


Disclosures: Ezra Cohen has received compensation from MSD and Roche for serving on advisory boards and serves on the Scientific Advisory Board of Pangea Biomed and Soteria. Cohen and J. Silvio Gutkind are members of the Scientific Advisory Board of io9. Gutkind is a consultant for Domain Therapeutics, Pangea Therapeutics and founder of Kadima Pharmaceuticals. Ludmil B. Alexandrov is a paid consultant and has a stake in io9. His wife is an employee of Biotheranostics, Inc. He is also the inventor of U.S. Patent 10,776,718 for source identification by non-negative matrix factorization and declares U.S. Provisional Applications with Serial Numbers: 63/289,601, 63/ 269,033 and 63/366,392. Webster K. Cavenee and Scott Lippman are co-founders of io9. Cavenee is a board member of Genetron Health and a founder of Interleukin Combinatorial Therapies and InVaMet. Lippman is a member of the Scientific Advisory Board of Biological Dynamics.

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