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Kanker kolorektal merupakan penyebab kematian tertinggi kedua akibat kanker setelah kanker paru-paru. Pada tahun 2018 terdapat 1,8 juta kasus baru kanker kolorektal dan 892.000 mortalitas secara global. Sebagian besar kasus kanker kolorektal baru terdeteksi pada stadium lanjut. Hal ini dikarenakan mayoritas pasien tidak merasakan gejala yang serius pada fase awal (asimtomatik). Dari total kasus, sekitar 25% pasien kanker kolorektal diketahui telah mengalami metastasis pada diagnosis awal dan 60% lainnya setelah menjalani terapi, sehingga memerlukan pengobatan yang lebih serius dan spesifik. Salah satu jalur metastasis kanker kolorektal adalah melalui aliran darah. Proses pembentukan pembuluh darah baru atau angiogenesis dipicu oleh Vascular Endothelial Growth Factor (VEGF). Interaksi antara VEGF-A dengan protein reseptor VEGFR-2 kinase menginisiasi proses angiogenesis yang dapat mempercepat penyebaran sel kanker. Beberapa senyawa telah berhasil dikembangkan untuk menghambat protein VEGFR-2 kinase, namun sebagian besar bersifat multi target dan menghasilkan berbagai efek samping. Pada penelitian ini, dilakukan studi in silico untuk menemukan inhibitor VEGFR-2 kinase terbarukan dengan selektivitas dan afinitas yang tinggi melalui perancangan obat berbasis fragmen. Simulasi penambatan molekul dilakukan berdasarkan struktur 3D VEGFR-2 kinase yang diperoleh dari Protein Data Bank (PDB ID: 1Y6A). Fitur farmakofor dirancang berdasarkan ligan standar Pazopanib dan 2-anilino-5-aryl-oxazole yang diambil dari basis data ChemSpider. Sebanyak 22.727 senyawa diambil dari pangkalan data PubChem dan dipilih 4 fragmen yang paling potensial untuk dilakukan penumbuhan fragmen. Selanjutnya, dari hasil penumbuhan fragmen dan simulasi penambatan molekul diperoleh 10 senyawa baru yang dinilai paling berpotensi menghambat protein VEGFR-2 kinase. Uji farmakologi dilakukan untuk mengetahui karakteristik fisikokimia dan toksisitas dari senyawa baru dengan menggunakan perangkat OSIRIS Data Warrior, SwissADME, pkCSM dan Toxtree. Berdasarkan interaksi molekular dan uji farmakologi diperoleh dua senyawa baru sebagai kandidat inhibitor VEGFR-2 kinase terbaik yaitu ligan 1070 dan ligan 1143.

 

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Colorectal cancer is the second leading cause of cancer death after lung cancer. As of 2018, there are an estimated 1,8 new diagnoses and 892.000 mortalities worldwide. Most of colorectal cancer cases were identified at an advance stage. Approximately 25% of patients with colorectal cancer have developed metastases in early diagnoses and another 60% after undergoing therapy that requires more serious and specific treatment. Metastasis was caused by angiogenesis which mediated by Vascular Endothelial Growth Factor (VEGF). Interaction between VEGF-A and receptor protein VEGFR-2 initiated the formation of new blood vessels that can accelerate the spread of cancer cells. Several compounds have been successfully developed to inhibit VEGFR-2 kinase, however most of them are multi target and result many side effects. In this research, in silico study was conducted to discover novel VEGFR-2 kinase inhibitor with high selectivity and affinity through fragment-based drug design. Molecular docking simulation was conducted based on 3D structure of VEGFR-2 kinase obtained from Protein Data Bank (PDB ID: 1Y6A). The standard ligands used in this research are pazopanib and 2-anilino-5-aryl-oxazole that acquired from ChemSpider databases. About 22.727 compounds were taken from PubChem database and 4 potential fragments were selected for fragment growing. From the result of fragment growing and molecular docking simulation, 10 new compounds that potential to inhibit VEGFR-2 kinase were obtained. Then pharmacological and toxicity tests are performed using OSIRIS Data Warrior, SwissADME, pkCSM and Toxtree. According to the molecular interaction and pharmacological tests, two new compounds are selected as the best candidate of VEGFR-2 kinase inhibitor that is ligand 1070 and ligand 1143.

 

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"Latar Belakang: Jumlah kasus KPKBSK diperkirakan 85% dari seluruh kasus kanker paru dan 40% diantaranya adalah jenis adenokarsinoma. Sebanyak 10%-30% pasien adenokarsinoma mengalami mutasi EGFR dan mendapatkan terapi EGFR-TKI. Mayoritas pasien KPKBSK memiliki respons dan toleransi baik terhadap terapi EGFR- TKI tetapi sebagian kecil pasien mengalami penyakit paru interstisial akibat EGFR- TKI. Penelitian ini bertujuan untuk mengetahui proporsi gambaran penyakit paru interstisial pada pasien KPKBSK dengan terapi EGFR-TKI di RSUP Persahabatan.Metode: Penelitian ini merupakan penelitian observasional analitik dengan pendeketan kohort retrospektif yang dilakukan bulan Januari 2021 hingga Juni 2022. Subjek penelitian adalah pasien KPKBSK yang mendapatkan terapi EGFR-TKI. Subjek penelitian dipilih sesuai kriteria inklusi dan eksklusi. Pengambilan data melalu data sekunder berupa rekam medis dan hasil CT scan toraks pasien yang kontrol di poliklinik onkologi RSUP Persahabatan.Hasil: Pada penelitian ini diperoleh 73 subjek penelitian, pasien KPKBSK dengan mutasi EGFR yang mendapatkan terapi EGFR-TKI di RSUP Persahabatan. Sebanyak 12 dari 73 subjek penelitian mengalami gambaran ILD yang dievaluasi berdasarkan CT scan toraks RECIST I dan II dengan karakteristik jenis kelamin laki-laki (22,2%), kelompok usia 40-59 tahun (19,4%), perokok (24,1%), indeks brinkman berat (42,9%) dan mendapatkan terapi afatinib (26,1%). Proporsi gambaran ILD pada pasien KBPKBSK dengan terapi EGFR-TKI adalah opasitas retikular (58,3%), parenchymal band (33,3%), ground-glass opacities (25%), traction bronchiectasis (25%) dan crazy paving pattern (8,3%). Hasil analisis bivariat dan multivariat menunjukkan tidak terdapat perbedaan antara faktor-faktor seperti jenis kelamin, usia, jenis EGFR-TKI, riwayat merokok, indeks brinkman, riwayat penyakit paru dan tampilan status terhadap gambaran ILD.Kesimpulan: Gambaran ILD pada pasien KPKBSK dengan terapi EGFR-TKI meliputi opasitas retikular, parenchymal band, ground-glass opacities, traction bronchiectasis dan crazy paving pattern. Tidak terdapat perbedaan bermakna secara statistik antara faktor-faktor yang memengaruhi terhadap gambaran ILD.

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Background: The number of cases of NSCLC is estimated around 85% of all lung cancer cases and 40% among them are adenocarcinoma. Approximately 10%-30% of adenocarcinoma patients have EGFR mutations and receive EGFR-TKI therapy. The majority of NSCLC patients have a good response and tolerance to EGFR-TKI therapy, but a small group of patients experience EGFR-TKI induced interstitial lung disease. This study aims to determine the proportion of features of interstitial lung disease ini NSCLC patients treated with EGFR-TKI at Persahabatan Hospital.

Methods: This study was an analytic observational with a retrospective cohort approach that was conducted from January 2021 until June 2022. The subject were NSCLC patients who received EGFR-TKI treatment. The inclusion and exclusion criteria were used to determine which subjects will be included in the study. Data collection through secondary data from medical record and chest CT scan results of patients controlled at oncology polyclinic at Persahabatan Hospital.

Result : In this study, there were 73 subjects of NSCLC with EGFR mutations and received EGFR-TKI therapy at Persahabatan Hospital. There were 12 out of 73 subjects had ILD features which were evaluated based on RECIST I and II chest CT scan with predominant of male (22.2%), age group 40-59 years old (19.4%), smokers (24.1%), severe Brinkman index (42.9%) and received afatinib (26.1%). The proportion of ILD features in NSCLC patients with EGFR-TKI therapy are reticular opacities (58.3%), parenchymal bands (33.3%), ground-glass opacities (25%), traction bronchiectasis (25%) and crazy paving pattern (8.3%). The results of bivariate and multivariate analyzes showed that there was no differences between factors such as sex, age, type of GEFR-TKI, smoking history, Brinkman index, history of lung disease and performance status with features of ILD.

Conclusion: Features of ILD in NSCLC patients with EGFR-TKI therapy include reticular opacities, parenchymal bands, ground-glass opacities, traction bronchiectasis and crazy paving pattern. There is no statistically significa"