Proteogenomic study may lead to more effective treatments for head and neck squamous cell carcinoma

Proteogenomic studies may provide a better understanding of how to match cancer patients with an effective treatment for their specific cancer.

Proteogenomic study may lead to more effective treatments for head and neck squamous cell carcinoma
Image Credit: Baylor College of Medicine.

Now, a new study has identified three molecular subtypes in head and neck squamous cell carcinoma (HNSCC) that could be utilized by scientists to establish a more suitable treatment for this medical condition.

The study, headed by Baylor College of Medicine, Johns Hopkins University, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) at the National Cancer Institute, has been published in the Cancer Cell journal.

Scientists profiled signaling pathways, phosphosites, and proteins in 108 human papillomavirus-negative HNSCC tumors to figure out how genetic abnormalities drive the response and behavior of tumors to treatments.

Today, only a few FDA-approved therapies exist for HNSCC, such as an epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) inhibitor and a couple of PD-1 inhibitors; however, the rates of response are still moderate.

In the latest research work, investigators aimed to determine why some patients are able to respond to specific therapies so that the patients can be matched to a suitable course of treatment.

We found three subtypes of head and neck squamous cell carcinoma, and each subtype may be good candidates for a different type of therapy—EGFR inhibitors, CDK inhibitors or immunotherapy. We also identified candidate biomarkers that could be used to match patients to effective therapies or clinical trials.”

Dr Bing Zhang, Study Lead Contact and Professor, Lester and Sue Smith Breast Center and Department of Molecular and Human Genetics, Baylor College of Medicine

Finding effective biomarkers

In one major finding, HNSCC patients were matched to EGFR mAb inhibitors. In 2006, the FDA approved an EGFR mAb drug, called Cetuximab, as the first targeted treatment for HNSCC. But the success rate for this kind of therapy is rather low. Besides this, the overexpression or amplification or of EGFR cannot predict the response to the EGFR mAbs drug.

In the new analysis, the team discovered that EGFR ligands, rather than EGFR itself, serve as the restricting factor for the activation of the EGFR pathway. During low concretions of ligands, the downstream pathway will not be activated, even if the EGFR protein is extremely overexpressed.

We proposed that the EGFR ligand should be used as a biomarker, rather than EGFR amplification or overexpression, to help select patients for the EGFR monoclonal antibody treatment.”

Dr Bing Zhang, Study Lead Contact and Professor, Lester and Sue Smith Breast Center and Department of Molecular and Human Genetics, Baylor College of Medicine

Zhang, who is also a member of the Dan L Duncan Comprehensive Cancer Center—a Cancer Prevention & Research Institute of Texas (CPRIT) Scholar—and a McNair Scholar at Baylor College of Medicine, added, “Tumors with high EGFR amplification do not necessarily have high levels of EGFR ligands, which may underlie their lack of response to EGFR mAb therapy.”

This hypothesis was confirmed by the researchers by examining earlier published data from a clinical trial and patient-derived xenograft models.

Moreover, when monitoring a crucial tumor suppressor, called Rb (retinoblastoma), the team made an incredible finding that indicates that the status of Rb phosphorylation could be a more improved indicator of a patient’s response to CDK4/6 inhibitor treatment.

The research work demonstrated that the several mutations in the genes controlling the CDK4/6 activity were neither needed nor adequate for CDK4/6 activation. The researchers observed that the CDK4 activity was optimally quantified through Rb phosphorylation measurements, thereby establishing a promising measure for selecting patients in CDK inhibitor clinical trials.

Immunotherapy insights

Furthermore, the researchers gained a crucial understanding of the effectiveness of immunotherapy. PD-1 inhibitors target the communication between PD-1 and PD-L1, which are both immune checkpoints; however, success rates of immunotherapy are rather low, even when the expression of PD-L1 is used for selecting patients.

The team also analyzed tumors that have high expression of the PD-L1 immune checkpoint and learned that when a tumor overexpresses this immune checkpoint, it also upregulates other kinds of immune checkpoints, thus enabling the tumor growth in spite of using PD-1 inhibitors.

Such an observation indicates that both the PD-1 and PD-L1 immune checkpoints, stimulated tumors with hot immune environments, may need numerous types of immunotherapy, which focus on different types of immune checkpoint proteins, to be effective.

On the other hand, tumors with cold immune environments are not exactly good targets for immunotherapy. Analysis of how a tumor turns into an immune-cold tumor demonstrated that the issue is caused by a defect in its antigen presentation pathway, in which numerous crucial gene constituents of the antigen presentation pathway were removed.

Therefore, while tumor antigens are being expressed, the immune system is unable to detect them on the cell surface and thus fails to trigger the defense system of the body against the tumor. Such deletions could serve as effective targets for upcoming treatments.

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.”

Dr Daniel W. Chan, Study Co-Corresponding Author and Director, Center for Biomarker Discovery and Translation, Johns Hopkins University School of Medicine

Dr Chan is also a professor of pathology and oncology at Johns Hopkins.

Source:
Journal reference:

Huang, C., et al. (2020) Proteogenomic insights into the biology and treatment of HPV-negative head and neck squamous cell carcinoma. Cancer Cell. doi.org/10.1016/j.ccell.2020.12.007.

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