İşlevsiz Hipofiz Nöroendokrin Tümörlerinin Tedavisinde Yeniden Konumlandırılmış Bir İlaç Adayı Olarak Maprotilin: Ağ Tabanlı Omik Odaklı Bir Yaklaşım

Öz

İşlevsiz hipofiz nöroendokrin tümörleri, sinsi bir ilerlemeye sahip olduğundan sadece klinik açıdan değil aynı zamanda hastalar için de büyük bir zorluk teşkil etmektedir. Zahmetli çalışmalar ve son teknoloji yöntemler bu hastalık hakkındaki bilgimizi geliştirse de, şu anda hastalığın kesin tedavisi için onaylanmış bir yöntem yoktur. Bu çalışma, yüksek verimli RNA dizileme analizlerinden elde edilen transkriptom verilerini kullanarak, NF-PitNET'te normalden farklı ifade desenleri gösteren, anlatımı önemli ölçüde değişmiş genleri belirlemeyi amaçlamıştır. Hastalığın patogenezi için gerekli unsurları ortaya çıkarmak amacıyla protein, transkripsiyon faktörü ve mikroRNA düzeylerindeki biyolojik ağlar oluşturulmuş ve topolojik olarak analiz edilmiştir. Bu analizler sonucunda AGO2, BCL2L2, BIRC5, BRCC3, CDC42, CUL3, E2F2, ESR1, ESR2, GIGYF1, JUN, KRAS, MDM2, NFKB1, PLEKHA4, RELA, RNF40, ve ZNF460 ağ bileşenleri biyolojik ağların merkezi elemanları olarak bulunmuş ve NF-PitNET'lerin sistem biyobelirteçleri olarak önerilmiştir. Merkezi elemanlarını tedavi hedefi olarak kulanan bir ilaç yeniden konumlandırma çalışması yapılmış ve valdekoksib, penfluridol, maprotilin hcl, mitoksantron, vorinostat, homoharringtonin, noretinodrel, strofint oktahidrat, bufalin ve digoksin dahil olmak üzere yeniden konumlandırılmış ilaç adayları ortaya çıkarılmıştır. Moleküler kenetlenme (docking) yöntemiyle yapılan in silico analizler, maprotilinin merkezî unsurlarla etkileşiminde, mevcut inhibitörlere kıyasla daha yüksek bağlanma afinitesi gösterdiğini ortaya koymuştur. Bu bulgular doğrultusunda, maprotilin, NF-PitNET tedavisinde umut vadeden yeniden konumlandırılmış bir terapötik ajan olarak önerilmektedir.

Anahtar Kelimeler

• transkriptomik
• RNA dizileme
• biyolojik ağlar
• ilaç repozisyonu
• hipofiz nöroendokrin tümörler

Maprotiline as a Repositioned Drug Candidate for the Treatment of Non-Functioning Pituitary Neuroendocrine Tumors: a Network-Based Omics-Oriented Approach

Öz

Non-functioning pituitary neuroendocrine tumors pose a great challenge not only for the clinic but also for patients since it has an insidious progression. Even though effortful studies and state-of-the-art techniques are improving our knowledge about this disease, no therapeutic modality is currently approved for the treatment. This study aimed to determine significantly altered genes that showed aberrantly expressed patterns in NF-PitNET using high-throughput RNA-sequencing transcriptome data. To uncover essential elements in disease pathogenesis, biological networks in protein, transcription factor, and microRNA levels were constructed and topologically analyzed. by drug prioritization for NF-PitNETs via a repositioning approach. The hub elemets of AGO2, BCL2L2, BIRC5, BRCC3, CDC42, CUL3, E2F2, ESR1, ESR2, GIGYF1, JUN, KRAS, MDM2, NFKB1, PLEKHA4, RELA, RNF40, and ZNF460 were proposed as systems biomarkers of NF-PitNET. A signature-based drug repositioning using hub elements as treatment targets unraveled repositioned drug candidates including valdecoxib, penfluridol, maprotiline, mitoxantrone, vorinostat, homoharringtonine, norethynodrel, strophantine octahydrate, bufalin, and digoxin. The efficiency of maprotiline was confirmed in silico via molecular docking and resulted in higher binding affinities with hub elements compared to their inhibitors. Maprotiline was proposed as a promising repositioned therapeutic for the management of NF-PitNETs.

Anahtar Kelimeler

• transcriptomics
• RNA-seq
• biological networks
• drug repositioning
• non-functioning pituitary neuroendocrine tumors

Kaynakça

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