F. Lardon PhD

Novel, rationally designed combination strategies, based on (phospho)-proteomic analyses, to enhance the response to cetuximab therapy in head and neck cancer

SUMMARY

Head and neck squamous cell carcinoma (HNSCC) is often characterised by overexpression of the epidermal growth factor receptor (EGFR), which is associated with aggressive disease and poor prognosis. While the EGFR-targeting antibody cetuximab initially showed promise for the treatment of HNSCC, the development of therapeutic resistance has hindered its efficacy. Therefore, this PhD thesis focused on unravelling mechanisms underlying cetuximab resistance and developing strategic combination therapies to overcome this resistance in HNSCC. Literature review illustrated the importance of the PI3K/Akt pathway as a potential target, with studies indicating its role in resistance to anti-EGFR targeting agents. Protein phosphorylation profiling indicated that increased Akt1/2/3 phosphorylation seems to be characteristic for acquired cetuximab resistance in HNSCC cell lines. Interestingly, we observed synergy between cetuximab and Akt inhibitor MK2206 or PI3K inhibitor buparlisib in multiple cell lines with different sensitivity to cetuximab. Furthermore, the combination treatment of cetuximab plus buparlisib altered the tumour microenvironment, increasing tumour immunogenicity by triggering immunogenic cell death markers and reducing immunosuppression. This research underscores the potential for novel, rationally designed combination therapies to combat cetuximab resistance in HNSCC and suggests avenues for further exploration, including triple combination therapies involving immune checkpoint inhibitors, offering hope for improved outcomes in cancer therapy.

(BELG J MED ONCOL 2024;18(6):244-247)

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Overcoming intrinsic and acquired resistance to EGFR-targeting agents in cancer treatment: focus on identification of predictive biomarkers and novel therapeutic strategies

SUMMARY

Targeted therapies that inhibit oncogenic signalling pathways are the key for precision medicine in cancer treatment. Research over the past decades has revealed that deregulated or increased signalling of the epidermal growth factor receptor (EGFR) plays an integral role in the development of various cancer types, including colorectal cancer (CRC) and head and neck squamous cell carcinoma (HNSCC). After initially promising results of EGFR-targeted therapies, it became clear that therapeutic resistance is a major clinical problem. Moreover, as an increasing number of patients are currently considered as candidates for treatment with EGFR-targeted therapy, identification of predictive biomarkers is extremely important. The objective of this PhD project was to unravel and overcome resistance to the EGFR-targeting agent cetuximab in CRC and HNSCC. Hereby, we focused on the identification of drug resistance mechanisms, novel drug targets and therapeutic strategies as well as predictive biomarkers.

The present study demonstrated that afatinib, a second-generation irreversible inhibitor of EGFR, HER2 and HER4, has the potential to overcome cetuximab resistance in CRC and HNSCC cell lines. Therefore, these data support the hypothesis that afatinib may be a promising therapeutic agent to treat CRC and HNSCC patients experiencing intrinsic or acquired cetuximab resistance. Furthermore, we found that increased phosphorylation of Akt seems to be characteristic for acquired cetuximab resistance in HNSCC. Although further confirmation in tumour samples of HNSCC patients is imperative, Akt appears a novel drug target to improve outcome after cetuximab treatment as well as a potential predictive biomarker for EGFR-targeted therapies in HNSCC patients. In this view, we encourage further studies that focus on targeting Akt in combination with cetuximab, as this may be a promising strategy to overcome drug resistance in HNSCC patients. These findings can form a solid basis for further experiments with advanced in vitro and in vivo models.

(BELG J MED ONCOL 2020;14(4):155–8)

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Unravelling the immunotherapeutic potential of CD70 as a target in solid malignancies

SUMMARY

Under normal conditions, CD70, member of the tumour necrosis factor family, is only transiently expressed on activated T and B cells. Instead, constitutive expression of CD70 has been described on malignant cells in a range of solid and haematological malignancies. Through its receptor, CD27, the expression of CD70 can facilitate evasion of the immune system by three important mechanisms: induction of T cell apoptosis, T cell exhaustion and increasing the amount of suppressive regulatory T cells. The general aim of this thesis was to investigate the role of CD70 in solid tumour types and explore promising combination strategies for anti-CD70 therapy. Thereby, we focused on the role of CD70 in non-small cell lung cancer and colorectal cancer.

(BELG J MED ONCOL 2019;13(2):54–59)

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Targeted therapy for the treatment of head and neck squamous cell carcinomas: hopes and pitfalls

Targeted therapy is a promising strategy for the treatment of head and neck squamous cell carcinoma and other cancers, which has been developed as a result of breakthroughs in molecular characterisation of carcinogenesis. It is thought to offer a higher therapeutic index and, therefore, to be associated with less toxicity than cytotoxic drugs. Unfortunately this kind of therapy also has weaknesses; in particular the long-term response rate is disappointing. This review will not only focus on the benefits of EGFR targeted agents in head and neck squamous cell carcinoma, but will also summarise its weaknesses.

(BELG J MED ONCOL 2015;9(5):175–78)

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Biomarkers for an effective and cost-effective use of anti-EGFR biotherapeutics for the treatment of head and neck cancer

As the epidermal growth factor receptor is expressed in up to 90% of all head and neck squamous cell carcinomas and initiates important signalling pathways in carcinogenesis, this receptor has emerged as a promising therapeutic target. Nevertheless, the challenge of drug resistance alongside treatment with epidermal growth factor receptor inhibitors remains. New results from our research group provide evidence that the RAS-MAPK signalling pathway is still activated despite upstream epidermal growth factor receptor blocking by cetuximab, an epidermal growth factor receptor targeting monoclonal antibody. DUSP5, DUSP6, AURKB, HB-EGF, IL8 and the transcription factor AP-1 were among the genes identified by us as likely contributing to cetuximab resistance. These novel findings provide new insights in the underlying mechanisms of anti-epidermal growth factor receptor therapeutic resistance in head and neck squamous cell carcinomas. Furthermore, these observations can form a solid basis for further in vivo and clinical studies on this topic, making advances in the treatment of head and neck squamous cell carcinomas.

(BELG J MED ONCOL 2015;9(2):74–6)

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Isolated lung perfusion as additional treatment for lung metastases

The golden standard for the treatment of lung metastases remains complete surgical resection. Prognostic factors for patients with lung metastases are histology, number of metastases and disease-free interval. However, the chance of recurrent disease in the treated lung remains high after complete resection, even in combination with systemic chemotherapy. Systemic toxicity limits the dose of the latter, resulting in only limited local pulmonary control. Therefore, new techniques are developed to deliver a high-dose of chemotherapy selectively into the lung, reducing the risk of systemic toxicity. One of these techniques is isolated lung perfusion, which is comparable with isolated limb perfusion. This experimental surgical technique allows delivery of a very high-dose of chemotherapy with or without biological response modifiers to the lung, without the risk of systemic exposure. Experimental studies with this technique have shown its superiority in achieving higher tissue concentrations of chemotherapy in the target organ as well as improved survival in comparison with systemic chemotherapy. As shown in several phase I studies, this technique is technically feasible with minimal morbidity and minimal impact on pulmonary function. In a recent phase II study, an improved local pulmonary control was found in comparison with the literature. This review discusses the current status of isolated lung perfusion as well as newer, less invasive techniques to deliver high-dose chemotherapy selectively to the lung.

(BELG J MED ONCOL 2015;9(1):5–10)

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