Glioblastoma multiform'da TRAIL duyarlılığını artıran yeni ilaçların taranması

Glioblastoma multiforme (GBM) is the most aggressive and frequent type of primary brain tumor. Even though only 1% of adult cancers are GBMs, their malignant nature makes them the fourth greatest cause of cancer deaths. Treatment of GBM is extremely difficult due to several factors. First, the tumor cells, despite their relatively rapid cell cycle, are quite resistant to conventional therapies. In addition, the blood–brain barrier (BBB) permeability makes it difficult to achieve the desired effect of chemotherapeutics without dose–limiting systemic side effects Current treatment options for GBM include surgery, radiation therapy and chemotherapy. However, development of resistance to these approaches is frequent. For this purpose, new treatment options are needed for GBM patients. Apoptosis, programmed cell death, plays a central role in the development and homeostasis of multicellular organisms. Two main characterized apoptosis pathways are defined in mammalian cells: extrinsic and intrinsic pathways. Intrinsic pathway includes the activity of mitochondria and is controlled by Bcl-2 protein family members. Extrinsic pathway is mediated by death receptors, which are a subgroup of the tumor necrosis factor (TNF) receptor superfamily. In cancers, including GBMs, apoptosis pathway is suppressed, and tumor cells adopt pathways to evade it. However, re-activating apoptosis by using extrinsic ligands can be a prominent therapeutic approach. As such, TNF-related apoptosis-inducing ligand (TRAIL) has the ability to induce apoptosis in tumor cells, but it does not have cytotoxicity on normal cells, which makes it a perfect candidate for GBM treatment. Although TRAIL is a prime therapeutic candidate, many cancer cells are intrinsically resistant and/or acquire resistance to TRAIL. The mechanism of TRAIL resistance is still not completely solved, but it is believed to be due to dysregulations at multiple levels from death receptors to executor caspases within the apoptotic pathway. TRAIL resistance can be overcome by combination therapies. Combination of TRAIL with chemotherapeutics, radiation or other novel therapeutic drugs is a promising approach based on several pre-clinical observations. In this thesis, we describe our approach of identifying novel TRAIL-sensitizing drugs among known and approved chemicals and utilizing high throughput screening (HTS) method. HTS is a method used for drug discovery, where large numbers of drug-like compounds are tested using robotic methods, data processing and control software, to identify promising leads. Drug repurposing is the application of known drugs to other uses, which takes off years required to develop a new drug and provides a drastic economic benefit. In addition, a repurposed drug already comes with the systemic toxicity knowledge, hence reducing cytotoxicity problems. With this in mind, a HTS with a chemical library consisting of 1200 Food and Drug Administration (FDA) approved drugs were utilized for investigating TRAIL sensitizers for GBM. Accordingly, we identified a class of drugs, called cardiac glycosides, with a novel TRAIL sensitizing function for GBM cells. We also investigated the downstream changes in apoptosis pathway components upon the application of this new class of drugs. Our results suggest that combination of cardiac glycosides and TRAIL can be a promising therapeutic approach for GBM patients.