Head and neck cancer (HNC) encompasses various types of cancer, with the most prevalent being head and neck squamous cell carcinoma (HNSCC). Treatment for HNC typically involves a combination of surgery, radiotherapy, and chemotherapy. However, these treatments often have severe side effects, and some patients are unable to complete the entire course of treatment. Furthermore, even after enduring such harsh therapies, approximately 60 percent of patients experience a relapse. The limited effectiveness of current treatments can be attributed, in part, to the significant genetic variations found in tumors among different patients. Consequently, the most appropriate therapy differs for each individual.
Rosemary Millen, one of the primary authors of a recent paper published in the journal Med, elucidates, “These treatments result in significant side effects, and some patients are unable to complete the treatment. Moreover, despite undergoing such rigorous treatment regimens, 60 percent of patients experience a recurrence.” The inadequacy of current therapies may be explained by the substantial genetic heterogeneity observed in tumors across patients. Therefore, there is a critical need for improved biomarkers—indicators that can be measured in each patient—to accurately determine the most suitable treatment. Ideally, adopting a personalized approach based on such biomarkers would spare patients from unnecessary burdens of ineffective treatments and lead to better prognoses,” explains Else Driehuis, the corresponding author of the paper.
Setting up a biobank
To advance personalized treatments, researchers have initiated the development of more accurate models that better represent the variability of tumors. As part of this endeavor, a biobank of head and neck cancer (HNC) organoids—miniature versions of patient tumors grown in the laboratory—was established. Rosemary Millen explains, “The ultimate aim of creating such a biobank is to utilize the organoids to inform personalized treatment decisions in clinical settings. However, before we can achieve that, we needed to investigate whether the response to treatment in the organoids aligns with the response observed in patients.”
Else Driehuis adds, “Willem de Kort, a co-author of the paper, successfully collected numerous samples from HNC patients at the UMC Utrecht. These samples were obtained from either diagnostic biopsies or surgical resections of the tumors, and the patients’ disease progression was followed. We had close collaboration with surgeons, oncologists, and radiologists throughout the project. It was truly a collaborative effort.”
The research team successfully grew HNC organoids from the patient samples and confirmed that these miniature tumors closely resembled the original patient tumors, displaying similar histological and genetic characteristics. Millen notes, “Subsequently, we treated the organoids with various types of therapies and assessed treatment effectiveness by measuring cell death within the organoids. The next step involved correlating these findings with treatment responses observed in patients.”
Comparing organoids and patients
Following the administration of radiotherapy to the organoids, the research team discovered a resemblance between the response of the organoids and the treatment responses observed in patients. “This suggests that the organoids have the potential to predict patient outcomes. The correlation between organoid and patient response was particularly evident in cases where patients received adjuvant radiotherapy, which involves using radiation in addition to surgical tumor resection. However, further investigation is required for cases where radiotherapy is used as the primary treatment,” explains Millen.
Furthermore, the researchers investigated the impact of chemoradiotherapy, a combined approach involving radiation and chemotherapy. Driehuis states, “Our findings demonstrate that two specific chemotherapy drugs, cisplatin and carboplatin, have a radiosensitizing effect in the organoids. This means that they enhance the sensitivity of tumor cells to radiotherapy. These results align with clinical observations and further emphasize the predictive potential of organoids in this treatment context.”
The team’s discoveries hold promising implications for the future of HNC patient care. One notable finding is that the drug cetuximab reduced the sensitivity of tumor organoids to radiotherapy. Driehuis explains, “This is surprising because cetuximab and radiotherapy are combined in the clinical treatment of certain HNC patients. In patients, it is challenging to discern the individual contributions of the drug and radiation therapy to the overall treatment effect. However, with the organoids, we can dissect these factors.”
“Our results align with recently published data indicating that the survival of patients treated with cetuximab and radiotherapy is worse compared to radiotherapy alone. Clinically, these findings suggest that it may be preferable to delay cetuximab treatment until after radiotherapy. Of course, this change in treatment timing would require rigorous testing in patients,” Driehuis adds.
Additionally, the team demonstrated that a PRMT5 inhibitor, a novel drug already undergoing clinical trials for other cancer types, could be effective for a subgroup of HNC patients. Millen explains, “Through DNA sequencing of the organoids, we explored the relationship between specific genetic mutations and treatment responses. Our findings indicated that tumors with a loss of the CDKN2A gene responded well to treatment with this novel drug. It would be highly intriguing to investigate whether this effect is also observed in patients, particularly considering that this mutation is present in over 50% of HNSCC cases.”
In conclusion, the team’s results emphasize the clinical significance of utilizing organoids derived from patient tumor tissue. One of the next crucial steps would involve designing a clinical trial to effectively incorporate organoids in guiding treatment decisions for HNC patients, as stated by Driehuis.
Source: Hubrecht Institute