Académie royale de Médecine de Belgique

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Prix Alexandre Straetmans (2012-2014) - Lauréates Mme Sebahat Ocak et Mme Sandra Schmitz (Présentation + Résumés)

PRÉSENTATION DE Mme S. OČAK et Mme S. SCHMITZ, LAURÉATES DU PRIX ALEXANDRE STRAETMANS (2012-2014)

par J. Boniver, membre titulaire

Présentation en attente

MOLECULAR DETERMINANTS OF LUNG CANCER PROGRESSION. FUNCTIONAL IMPLICATIONS OF THE POLYMERIC IMMUNOGLOBULIN RECEPTOR AND THE FOCAL ADHESION KINASE

par Mme le Dr Sebahat OČAK (UCL)

RESEARCH GOAL OF THE THESIS

Lung cancer is the first cause of cancer-related death worldwide. The molecular steps leading to lung cancer development and progression are still poorly understood. This translated into the absence of molecular strategies for early detection, the lack of targeted therapies, and therefore a poor prognosis for lung cancer that has not significantly changed over the last 20 years.
The central hypothesis supporting this thesis work is that lung cancer development and progression is the consequence of the acquisition of multiple genetic alterations including mutations and copy number aberrations, and of the loss of tight regulatory mechanisms maintaining cellular physiological processes such as proliferation, apoptosis, and migration. The discovery of these oncogenic alterations and lost key regulatory proteins or pathways should lead to a better understanding of the disease process, and to novel diagnostic and therapeutic interventions, as well as new prognostic lung cancer biomarkers. Ultimately, this may decrease the mortality of this disease.
We approached this problem by multiple ways. The two central approaches we took were: 1/ a gene-centric approach with the investigation of the functions of key molecular determinants and 2/ the use of high-throughput technologies to identify biomarkers of disease with potential diagnostic, therapeutic, prognostic, and biological endpoints in the hope to alleviate suffering from lung cancer.


SUMMARY OF THE ORIGINAL RESEARCH PROJECTS

First, we hypothesized that the loss of the polymeric immunoglobulin receptor (pIgR) expression is an early event in lung cancer development and that the biology of this receptor may be implicated in tumorigenesis. This work stems from observations made in Professor Sibille’s Laboratory looking at the role of pIgR in airway biology, particularly host defense mechanisms in chronic obstructive pulmonary disease where pIgR was found to be downregulated, such as in lung cancer. We made the observation that not only pIgR expression was lost early in lung cancer development but also that restoring its function in cancer cells inhibited cellular proliferation 1. The mechanisms of this observation are indirect and seem to implicate loss of cellular differentiation, loss of cellular polarization, and epithelial mesenchymal transition.
Next, we turned to an unbiased genome-wide approach (as opposed to a gene-centric/candidate-based approach to investigate the role of pIgR) to explore small-cell lung cancer (SCLC) pathogenesis in an unbiased way by interrogating the cancer genome. We focused on SCLC because of the lack of progress in this devastating disease. We analyzed SCLC primary tumors by array comparative genomic hybridization based on the hypothesis that DNA copy number aberrations would allow the identification of molecular pathways of SCLC progression. This work led to the identification of the focal adhesion pathway derangement in SCLC and to a series of functional and translational studies to establish a role of the focal adhesion kinase (FAK) activation in SCLC adhesion and migration 2, and to correlate its expression with clinical outcomes 3.
Finally, we undertook a high-throughput proteomic analysis to discover new molecular diagnostic and therapeutic biomarkers of SCLC. The goal was to identify membrane-specific protein biomarkers at the surface of SCLC that could be later developed into molecular imaging strategies or targeted therapies. We therefore analyzed membrane-associated protein extracts from immortalized normal bronchial epithelial, NSCLC, and SCLC cell lines by difference gel electrophoresis. This work led to the discovery of new candidate diagnostic or therapeutic biomarkers.
Various high-throughput technologies being used in this work, we also reviewed the scientific literature related to these technologies inlung cancer 4, 5.



REFERENCES

1.    Ocak S, Pedchenko TV, Chen H, et al. Loss of polymeric immunoglobulin receptor expression is associated with lung tumorigenesis. Eur Respir J 2011;Epub ahead of print.
2.    Ocak S, Yamashita H, Udyavar AR, et al. DNA copy number aberrations in small-cell lung cancer reveal activation of the focal adhesion pathway. Oncogene 2010;29(48):6331-6342.
3.    Ocak S, Chen H, Callison C, et al. Expression of focal adhesion kinase in small-cell lung carcinoma. Cancer 2011;Epub ahead of print.
4.    Ocak S, Chaurand P, Massion PP. Mass spectrometry-based proteomic profiling of lung cancer. Proc Am Thorac Soc 2009;6:159-170.
5.    Ocak S, Sos ML, Thomas RK, et al. High-throughput molecular analysis in lung cancer: insights into biology and potential clinical applications. Eur Respir J 2009;34:489-506.



WINDOW OPPORTUNITY STUDIES IN HEAD AND NECK CANCER TO TARGET THE INSULIN GROWTH FACTOR-1 AND THE EPIDERMAL GROWTH FACTOR RECEPTORS : FROM BED TO BENCH

par Mme le Dr Sandra SCHMITZ (UCL)


Despite progress in the management of patients with squamous cell carcinoma of the head and neck (SCCHN), the mortality rate of patients with advanced disease remains high.

Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) have shown clinical benefits in the palliative and curative settings. However, only a minority of patients with recurrent or metastatic (R/M) SCCHN will have meaningful tumour regression with these agents, and virtually all will develop acquired tumour resistance after a few months of treatment. Therefore, research and development into new compounds that target activated pathways in SCCHN is of interest. Moreover, clinical study designs that allow the collection of pre- and post-treatment tumour samples are important to better understand the molecular mechanisms involved in treatment response or resistance.

The first part of this work investigated the antitumour activity of figitumumab, a fully human monoclonal antibody IgG2 subtype which targets the insulin growth factor-1 receptor (IGF-1R) overexpressed in SCCHN, and which is associated with poor prognosis. In a phase II trial, patients with palliative SCCHN were treated with figitumumab IV 20 mg/kg, every three weeks. Despite encouraging preclinical results, figitumumab did not show any relevant clinical benefit. Further investigations supported cross-talk between the IGF-1R and the EGFR and upregulation of cIAP2, an inhibitor of apoptosis upregulated by the Akt signaling pathway.

Unfortunately this kind of study design is unlikely to fully exploit the anti-tumour potential of  targeted agents because patients with palliative disease have received multiple treatment regimens (RT/CT/CRT/Surgery) leading to multifactorial resistance. In a second part, we investigated cetuximab in the pre-operative window period in treatment-naïve SCCHN patients selected for primary curative surgery. 18FDG-PET, MRI, tumour biopsies and plasma samples were performed or collected before and after cetuximab. We observed 18FDG-PET partial response (EORTC guidelines) in 90% of the patients included in the cetuximab group versus 0% in the control group. Delta maximal standardized uptake values (ΔSUVmax) correlated with tumour cellularity on the surgical specimens (p=0.0004). Decrease of the tumour cell density and increase of the extracellular matrix were also recorded by diffusion MRI acquisitions and perfusion CT. Analysis of microarray data confirmed modifications in tumour composition with increased expression of matrikines and genes associated with cancer-associated fibroblasts (CAFs) and epithelial to mesenchymal transition (EMT). Independently from metabolic modifications, we identified two clusters of patients with different expressions of EMT markers, indicating that phenotypical tumour modifications are not correlated to initial clinical response and that one potential acquired resistance mechanism to cetuximab could be related to a mesenchymal cell phenotype.

Further, we investigated the inflammatory process by examining tumour infiltration by immune cells after cetuximab. We observed increased infiltration of the tumour by cytotoxic T cells. In addition, increased expression of genes implicated in complement-derived cytotoxicity was also observed. This lead to the hypothesis that NK derived ADCC is probably not the only immunologic mechanism of cetuximab in SCCHN that should be investigated.