Head and neck cancer organoids as a step towards personalized treatments

Head and neck cancer (HNC) is an overarching term used for several types of cancer, including the most common form called head and neck squamous cell carcinoma (HNSCC). HNC patients can be treated with a combination of surgery, radiotherapy and/or chemotherapy. Nevertheless, treatment is not always effective. Rosemary Millen, shared first author of the paper, explains: “These treatments cause serious side-effects and some patients are therefore unable to finish the treatment. And even after going through such a harsh treatment, 60 percent of patients relapse.” The limited efficacy of treatments might be explained in part by the fact that the genetic makeup of the tumor differs strongly between patients. As a result, the most suitable therapy is different for each patient. “Clinicians currently have limited tools to properly distinguish this. There is therefore an urgent need for better biomarkers: indicators that we can measure in each individual patient in order to determine from which treatment they would benefit most. Ideally, such a personalized approach would prevent you from unnecessarily burdening patients with treatments that might not work, and lead to a better prognosis,” explains Else Driehuis, corresponding author of the paper.

Setting up a biobank

A first step towards such personalized treatments is to develop better models that reflect tumor variability more accurately. The researchers therefore set up a biobank of HNC organoidsMiniature organs that can be cultured in the laboratory. Organoids mimic the shape and function of an actual organ. Researchers use the structures to, for example, study the effects of medication on diseased organs.: miniature versions of patient tumors, grown in the lab. Millen: “Ultimately, the goal of such a biobank would be to use the organoids to guide personalized treatment decisions in the clinic. Of course, before we can do that, we first needed to investigate whether the treatment response in the organoids correlates with the response seen in patients.” Driehuis adds: “Willem de Kort, shared first author of the paper, was able to collect many HNC patient samples at the UMC Utrecht. He collected tumor tissue from these patients, either during diagnostic biopsies or surgical resections of the tumor, and followed their disease course. We closely collaborated with surgeons, oncologists and radiologists throughout the project. It was a real team effort.” The team was able to grow HNC organoids from the patient tissues and confirmed that these ‘mini tumors’ closely resembled the patient tumors, as they retained the same histological and genetic features. Millen: “We then treated the organoids with several therapy types and measured treatment efficacy by determining how many cells in the organoids died. The next step was to correlate this to treatment response in patients.”

Clinical implications

Some of the discoveries made by the team could have implications for HNC patients in the near future. For example, they showed that the drug cetuximab made the tumor organoids less sensitive to radiotherapy. Driehuis explains: “This is surprising, because the combination of this drug and radiotherapy is given to some HNC patients in the clinic today. In patients, it’s difficult to distinguish the individual contributions of the drug and the radiation therapy to the overall effect of this combination treatment, but in the organoids we can pull that apart. Our results fit with recent published data that show that survival of patients treated with cetuximab and radiotherapy is worse compared to treatment with radiotherapy alone. The clinical implication of these findings would be that it’s better to wait with cetuximab until after radiation therapy, but this change in timing of treatment is something you would need to test in patients of course.” The team also showed that a so-called PRMT5 inhibitor, a novel drug already in clinical trials for other cancer types, could be effective for a subgroup of HNC patients. Millen: “We sequencedA technique that is used by researchers to determine the genetic code of DNA or RNA. This information can be used in various ways. In disease research, sequencing may be used to trace changes in the genetic code. This could for example elucidate the cause of the disease. the DNA of the organoids, to investigate the relationship between specific genetic mutationsErrors in the DNA. Mutations can, among other things, arise if the DNA is copied incorrectly or through external influences. For example, tumor cells often contain mutations that are beneficial for their growth. and the response to treatments. By doing so, we found that tumors with loss of the geneA small piece of DNA with a specific function. For example, genes determine which color our eyes have and whether we have curly or straight hair. In a human cell, the DNA contains about 30.000 genes, each having a specific function. Genes are hereditary and can therefore be passed on to offspring. CDKN2A were responsive to treatment with this novel drug. It would be very interesting to see whether this effect is also found in patients, especially since this mutation is present in over 50% of HNSCC cases.” Driehuis concludes: “Taken together, our results highlight the clinical relevance of organoids derived from patient tumor tissue. One of the next steps would be to design a clinical trial, to really use the organoids to guide treatment decisions in HNC patients.”

This study was funded by the Oncode Clinical Proof of Concept fund.

Publication

Patient-derived head and neck cancer organoids allow patient treatment stratification and serve as a platform for biomarker validation and identification. Rosemary Millen*, Willem W.B. de Kort*, Mandy Koomen, Gijs J.F. van Son, Roan Gobits, Bas B.L. Penning de Vries, Harry Begthel, Maurice Zandvliet, Patricia A.H. Doornaert, Cornelis P.J. Raaijmakers, Maarten H. Geurts, Sjoerd G. Elias, Robert J.J. van Es, Remco de Bree, Lot A. Devriese, Stefan M. Willems, Onno W. Kranenburg, Else Driehuis and Hans Clevers. Med, 2023.

* Authors contributed equally