towards improved death receptor targeted therapy for ... - TI Pharma

Chapter 1
GENERAL INTRODUCTION
Cancer is one of the leading causes of death across the world. Recently, it has overtaken
heart disease from its number one position as the world’s most deadly disease. Among
the different cancer types, lung cancer is one of the most prevalent ones, with each year
approximately 1.1 million patients succumbing to this devastating disease [1]. The main
cause of lung cancer is exposure to tobacco smoke, which accounts for 85% of all lung
cancer cases. Radon gas, asbestos and genetic factors are also causes of lung cancer
development. Lung cancer can be divided into two histological subtypes, namely small cell
lung cancer (SCLC), which represents 15‐20% of all lung carcinomas and non‐small cell
lung cancer (NSCLC), which accounts for 80‐85% of all lung cancer cases. NSCLC can be
divided into three major types, i.e. squamous cell carcinoma, adenocarcinoma and large‐
cell carcinoma [2].
NSCLC is often diagnosed at an advanced stage of disease contributing to a poor
prognosis. At early stages of the disease, i.e. in the absence of metastases, removal of the
primary tumor by surgery gives rise to relatively good prognosis. The median 5‐year
survival rate is 50 to 60% for local stage 1A and 40% for stage 1B. At later stages with local
or distant metastases cure rates drop drastically. The five‐year overall survival of stage IIIB
NSCLC is 5‐8% and for patients with stage IV it is only 1% [3]. The first‐line treatment of
advanced NSCLC is platinum‐based chemotherapy, such as cisplatin or carboplatin in
combination with a third generation cytotoxic drug, gemcitabine, pemetrexed, paclitaxel,
docetaxel, etoposide or vinorelbine. However, only partial responses can be achieved in
just 30‐40% of the cases and severe side effects are often observed [4]. In recent years a
lot of progress has been made with the introduction of targeted therapy for NSCLC
patients. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as
gefitinib (Iressa) and erlotinib (Tarceva) proved to be quite effective, but only in a small
group of patients; Japanese women, non‐smokers and patients with adenocarcinoma.
These patients carry specific activating mutations in the tyrosine kinase domain of the
EGFR leading to constitutive activation of this pathway, and which correlated with clinical
response to EGFR inhibitors [5;6]. Recently, the anaplastic lymphoma kinase (ALK) tyrosine
kinase (TK) receptor has emerged as a relevant biomarker and therapeutic target in
NSCLC. ALK inhibitors, such as crizotinib, will probably benefit only a subgroup of NSCLC
patients with an EML4‐ALK fusion gene [7;8]. Despite these promising advancements in
the treatment of groups of NSCLC patients, for many NSCLC patients new treatment
approaches need to be discovered.
Apoptosis‐targeted therapy provides an interesting strategy for the treatment of various
cancers, including lung cancer. In particular, TNF‐related apoptosis‐inducing ligand
(TRAIL), which belongs to the Tumor Necrosis Factor (TNF) superfamily, is a promising
cancer therapeutic as it targets tumor cells in a selective way through specific TRAIL
receptors. Currently, different TRAIL receptor targeting agents are being evaluated in
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