ONCOTHESIS

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)

Geriatric oncology: targeting older patients with cancer

SUMMARY

As the cancer population ages, treatment decisions in the older patients should not only be guided by the tumour characteristics but also by patient characteristics. The performance of a comprehensive geriatric assessment as well as a health related quality of life evaluation are important in order to deliver the optimal personalised care in older patients with cancer. The current PhD thesis focused on the use of screening tools, geriatric assessment and interventions as well as on health-related quality of life in older patients with cancer.

(BELG J MED ONCOL 2020;14(3):106–8)

Boosting anticancer immunity with radiotherapy

SUMMARY

Preclinical and early clinical data indicate that stereotactic body radiotherapy (SBRT) could work synergistically with checkpoint inhibitors and increase response rates. Given the potential synergistic effect between both treatments, the associated toxicity might also be increased. We conducted two phase I trials combining SBRT with ipilimumab (n=13) or pembrolizumab (n=18) in metastatic/inoperable melanoma and metastatic urothelial carcinoma respectively. To evaluate the effect of SBRT timing, patients were randomised to either sequential or concurrent SBRT in the latter trial. To assess early efficacy, a phase II trial of SBRT and nivolumab was conducted in metastatic/inoperable melanoma (n=20). Our data shows that SBRT combined with ipilimumab, nivolumab or pembrolizumab is safe and might increase efficacy in a subset of patients.

(BELG J MED ONCOL 2020;14(1):28–30)

HER2 overexpression in gastroesophageal adenocarcinoma, prognostic and predictive value and diagnostic approach

SUMMARY

Gastric (including gastroesophageal junction) adenocarcinoma ranks top three in global cancer mortality. Between 4–30% of patients have human epidermal growth factor receptor 2 (HER2) driven disease, and targeting HER2 receptor signalling improved prospects in metastatic setting. HER2 status is assessed by immunohistochemistry and in situ hybridisation. However, determination and interpretation of HER2 status remains challenging due to intra- and intertumoral heterogeneity and lack of data on the biological relevant cut-off. Currently, only trastuzumab is approved for treatment of HER2 amplified advanced gastric cancer. The strength of HER2 amplification at baseline and after progression should be integrated in future prospective randomised trials. HER2 loss occurs predominantly in cases with initial moderate immunostaining for HER2 and can lead to clinical resistance to trastuzumab. We review the use of liquid biopsies as an alternative to traditional tissue biopsies to overcome heterogeneity and to allow monitoring the dynamics of the plasma HER2 status. We believe that early detection of plasma HER2 loss can identify patients at risk for loss of response to anti-HER2 therapy. Based on a clinical case, we tried to define the implications and clinical relevance of HER2 positivity. We illustrate the usefulness of re-determination of the HER2 status in metastatic lesions after disease progression and provide the prospects of non-invasive testing.

(BELG J MED ONCOL 2019;13(4):135–141)

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)

Novel therapeutic molecular targets in lung cancer: non-V600 mutant and mutant

In three sequential studies, we pre-clinically investigated several previously unexplored lung cancer-derived BRAF mutations as well as a HER3 mutation and their response to clinically available targeted therapeutics. During the FIELT I clinical study at UZ Brussel, in which 229 non-small-cell lung carcinoma patients were prospectively investigated at the genomic level, twelve patients (5.2%) were identified to harbour a BRAF mutation in their tumour and one patient found to harbour a novel HER3 mutation. As opposed to melanoma, 75% of these non-small-cell lung carcinoma-derived BRAF mutations were non-V600. RAF inhibitors have only been clinically developed against BRAF V600 mutations because of concerns of paradoxical effect in non-V600 mutant cancers. The status of non-V600 mutations with regards to BRAF inhibition effects was unknown. We functionally analysed thirteen of such tumour-derived BRAF non-V600 mutations and demonstrated that all types of BRAF mutations cause pathway activation and are sensitive to clinically relevant doses of a combination of type I RAF-inhibitor (dabrafenib) and that paradoxical pathway activation is abrogated by MEK-inhibition (trametinib). This entails that dual inhibition of non-V600 mutations is effective and safe. Further, we investigated the comparative efficacy of two modes of RAF inhibition (type I vs type II) in suppressing mutant BRAF-induced ERK signalling. Our preclinical findings in non-V600 BRAF expressing cellular models suggest that the type II RAF-inhibition (AZ628) has more potential than the type I RAF-inhibition (dabrafenib), both as single agent and combined with MEK inhibition in suppressing the ERK pathway independent of the BRAF mutation type. We also explored a novel somatic lung cancer-derived V855 HER3 mutation. Our study provided evidence for oncogenicity of V855 HER3 in a HER2 and ligand-dependent manner, in murine and human cell lines. Further, we showed that the given V855A HER3 mutation predicts sensitivity to the clinically available HER-targeting therapeutic afatinib. Our findings support the clinical investigation of non-V600 BRAF mutated lung or other cancers with dual RAF and MEK inhibition and HER3 mutant cancers with afatinib.

(BELG J MED ONCOL 2019;13(1):31–34)

Multimodality treatment for high-risk prostate cancer: New perspectives

High-risk prostate cancer represents the most aggressive form of the disease worldwide. In the past it was largely treated without curative intent but during the last years there has been a paradigm shift with an increase of curative procedures (particularly radical prostatectomy) for high-risk patients and, vice versa, active surveillance for low-risk disease. For this reason the high-risk group represents the novel target for contemporary research. The pre-operative risk groups are considered homogeneous in terms of prognosis and therapeutic response but there are grey zones within each group that have not been adequately studied. The main hypothesis of this PhD thesis (ISBN-NUMBER: 9789082757606 for the printed version and 9789082757613 for the e-version) is that not all high-risk prostate cancer patients have the same outcomes after surgery and also not the same response to multimodality therapies. In this context, novel treatments or their combinations should be tested. We analysed the largest high-risk database in the world demonstrating that not all high-risk patients after surgery have the same outcome according to their postoperative pathologic features. The European Multicentre Prostate Cancer Clinical and Translational Research group classifier was then defined as three different prognostic groups to predict cancer specific death. Interestingly, patients in these groups did not respond homogenously to adjuvant radiotherapy and/or androgen deprivation therapy. We also analysed the survival impact of neoadjuvant hormonal therapy before surgery, showing that patients who need adjuvant radiotherapy and were exposed to neoadjuvant hormonal therapy have the best prognosis. This outcome opens new perspectives for neoadjuvant treatment with or without other treatment combinations. The ARNEO trial is a phase II randomised, double blind, placebo controlled trial to study the association of apalutamide and degarelix before surgery for intermediate and high-risk disease.

(BELG J MED ONCOL 2018:12(3):130–132)