Cancer Database Paves the Way for Precision Medicine Therapies

Researchers from the Johns Hopkins departments of oncology and pathology, the Johns Hopkins Kimmel Cancer Center, the Johns Hopkins University (JHU) School of Medicine, and 18 other organizations around the US and Poland have compiled a database of head and neck cancers to speed the development of precision medicine therapies.

The database is believed to be the most comprehensive molecular characterization to date of the most common type of head and neck cancer. With the database, researchers clarified the contribution of key cancer-associated genes, proteins, and signaling pathways in these cancers, as well as proposed possible new treatment avenues.

In a study published in Cancer Cell, researchers noted that head and neck squamous cell carcinomas (HNSCCs) are the sixth most common malignancy worldwide. HNSCCs arise in the cells that line the upper aerodigestive tract, including the lips, mouth, tongue, nose, throat, vocal chords, and part of the esophagus and windpipe.

HNSCCs can be classified into HPV-associated and HPV-negative subtypes. About 75 percent of all HNSCCs are HPV-negative, meaning they have distinct molecular profiles and significantly worse prognoses.

Most patients are treated with surgery, chemotherapy, and radiation. While targeted agents – like an epidermal growth factor receptor (EGFR) monoclonal antibody inhibitor and two PD-1 immune checkpoint inhibitors – have been approved by the FDA, overall response rates have been moderate.

Until now, researchers have lacked a complete understanding of how genetic aberrations drive tumor types. Experts have also had limited ability to translate genomic and transcriptomic findings into improved HNSCC treatment.

Researchers analyzed tumors from 108 patients who had not yet received cancer treatment, as well as 66 samples of healthy tissue surrounding the tumors. The team aimed to systematically catalogue HPV-negative HNSCC-associated proteins, phosphosites (areas where they are modified by phosphate groups) and signaling pathways, finding three distinct subtypes of HNSCCs.

The first subtype researchers identified, called CIN, showed the worst prognosis. This subtype was associated with the larynx, a strong history of smoking and high instability of chromosomes. Because this subtype was associated with frequent aberrations of the CCND1 and CDKN2A genes, and high activity of the enzymes CDK4 and CDK6, this type of cancer may respond best to anti-cancer drugs called CDK4/6 inhibitors.

The second subtype, called Basal, showed protein elevations of several basal factors, the most basic set of proteins needed to activate gene transcription. Researchers characterized this subtype by high activity in a signaling pathway called EGFR and high expression of molecules called AREG and TNFA, which attach to the EGFR tumor protein.

The team concluded that these cancers may respond best to anti-cancer drugs called monoclonal antibodies that are aimed at EGFR.

The third subtype, called Immune, was discovered among tumors in people who did not smoke and showed high expression of multiple immune checkpoint proteins. Researchers believe that these tumors may respond to anti-cancer drugs called immune checkpoint inhibitors. Overall, 32 percent of CIN tumors, 62 percent of Basal tumors, and 83 percent of Immune tumors had high potential for the suggested treatments.

The team also found two modes of activation of EGFR, suggesting a new strategy to stratify HNSCCs based on the number of molecules bound to EGFR, for effective treatment with monoclonal antibody drugs that enlist the natural immune system to fight cancer.

The group also noted that widespread deletion of immune modulatory genes among these cancers accounts for a loss of ability to produce an immune response.

“This study extends our biological understanding of HPV-negative HNSCCs and generates therapeutic hypotheses that may serve as the basis for future studies and clinical trials toward molecularly guided precision medicine treatment of this aggressive cancer type,” said Daniel Chan, PhD, principal investigator, a professor of pathology and oncology, and director of the Center for Biomarker Discovery and Translation at JHU School of Medicine.

These findings have critical implications for head and neck cancer precision medicine treatments. The research team plans to uncover the properties of HPV-positive HNSCCs.

“Previously, patients would be treated using different options, but there was no systematic way to know which treatment would be the best option for certain patients,” said Hui Zhang, PhD, co-principal investigator of the study, professor of pathology and oncology, and director of the Mass Spectrometry Core facility at JHU School of Medicine.