Patient-derived head and neck cancer organoids could help discover new therapies

Researchers from the Organoid Group (Hubrecht Institute) and UMC Utrecht have developed a biobank with organoids derived from patients with head and neck cancer (HNC). They used this biobank to validate known biomarkers of HNC and found that treatment responses in the organelles matched those seen in patients. The results of the study will be published in Med on May 12, 2023 and could help inform treatment decisions and discover new therapies for HCN patients in the future.

Head and neck cancer (HNC) is an umbrella term used to refer to several types of cancer, including the most common form called head and neck squamous cell carcinoma (HNSCC). HNC patients may be treated with a combination of surgery, radiotherapy, and/or chemotherapy. However, treatment is not always effective. “These therapies cause serious side effects and so some patients are unable to finish treatment. Even after undergoing such aggressive treatment, 60 percent of patients relapse,” explains Rosemary Mellen, author of the first paper. Limited effectiveness The treatments may be explained in part by the fact that the genetic makeup of the tumor varies strongly between patients. As a result, the most appropriate treatment for each patient varies.

Clinicians currently have limited tools to correctly distinguish this. Better biomarkers are therefore urgently needed: indicators that we can measure in each individual patient in order to determine which treatment they will benefit most from. Ideally, this personalized approach will prevent you from unnecessarily burdening patients with treatments that may not work, and lead to better prognosis.”

Else Driehuis, corresponding author of the paper

Create a biobank

The first step towards such personalized therapies is to develop better models that more accurately reflect tumor variability. So the researchers created a biobank of HNC-like organoids: miniature copies of patients’ tumors, grown in the lab. Mellen: “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 could do that, we first needed to investigate whether the treatment response in the organoids correlated with the response observed in patients.” “. Drehes adds: “William de Kort, joint first author of the paper, was able to collect many samples from HNC patients at UMC Utrecht. He collected tumor tissue from these patients, either during diagnostic biopsies or surgical removal of the tumour, and traced them for the course of the disease. We collaborated closely 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’s tissue and confirmed that these “mini-tumours” were very similar to the patient’s tumors, as they retained the same histological and genetic features. Melin: “We then treated the organoids with several types of therapy and measured the effectiveness of the treatment by determining how many cells had died in the organoids. The next step was to correlate this with the patients’ treatment response.”

Compare memberships and patients

After treating the organoids with radiotherapy, the team showed that the organelle response was similar to the patients’ treatment responses. “Thus organoids have the potential to predict patient outcomes. A correlation between organoids and patient response was present for patients receiving adjuvant radiotherapy, ie radiation is used in addition to surgical removal of the tumor. In cases where patients receive radiotherapy as initial treatment, we need more of investigating this,” Mellen explains. The researchers also studied the effect of radiochemotherapy, which is a combination of radiation and chemotherapy. “We show here that two specific chemotherapy drugs, cisplatin and carboplatin, have a radiosensitizing effect in organoids. This means that it makes tumor cells more sensitive to radiotherapy. These findings are consistent with what we see in the clinic, and thus underscore once again the predictive potential of organoids. in this place,” says Drehees.

Clinical implications

Some of the team’s discoveries may have implications for HNC patients in the near future. For example, they showed that cetuximab makes organoid tumors less sensitive to radiation therapy. 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 hard to distinguish the individual contributions of drug and radiotherapy to the overall effect of this combination therapy, but in organelles we can tease that out.” “Our results are consistent with recent published data showing that the survival of patients treated with cetuximab and radiotherapy is worse compared to radiotherapy alone. It is best to wait with cetuximab until after radiotherapy, but this change in treatment timing is something that you will need to test in patients of course.” . The team also showed that a so-called PRMT5 inhibitor, a new drug in clinical trials for other types of cancer, could be effective for a subset of HNC patients. Melin: “We sequenced the DNA of the organoids, to investigate the relationship between specific gene mutations and response to treatments. By doing this, we found that tumors that lose the gene CDKN2A They were responding to treatment with this new drug. It will be very interesting to see if this effect is also present in patients, especially since this mutation is present in more than 50% of HNSCC cases. napkin. One of the next steps will be to design a clinical trial, to really use memberships to guide treatment decisions in HNC patients.”

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