Masalah barah paru-paru
Perhaps it is because of the direct feeling of the respiratory system. As the haze continues, we feel more and more people suffering from lung cancer around us. Indeed, lung cancer is the fastest growing malignant tumor in the world. The incidence and mortality of kanser paru-paru are the first among men, and the incidence and mortality of women are the second. Every year on November 17th is the “International Lung Cancer Day”, and 2015 is the “First Year of Precision Medicine”. We hope that on this special day, we will pass on more lung cancer knowledge to people with lung cancer patients around us: lung cancer is not Incurable disease, scientific prevention and treatment of lung cancer, starting from understanding lung cancer.
Penyebab kanser paru-paru
The main causes of lung cancer include smoking, environmental pollution, occupational exposure, chronic lung disease, and genetic susceptibility. Among them, smoking is the first high-risk factor for the incidence of lung cancer. More than 80% of lung cancers are considered to be caused by smoking, and smokers are more than 10 times more likely to develop lung cancer than non-smokers. Women who do not smoke will have a 30% increased risk of lung cancer because their husband smokes. In particular, the “three 20” population, that is, people who have smoked for more than 20 years, people who have started smoking before the age of 20, and people who smoke more than 20 cigarettes a day are all high-risk groups for lung cancer. Because of very high number of smoker’s in India, incidence of lung cancer here is very high.
Faktor persekitaran seperti merokok, pendedahan pekerjaan, dan pencemaran alam sekitar akan mempunyai "patogenisitas" yang berbeza bagi orang dengan latar belakang genetik yang berbeza; sebagai contoh, beberapa orang memenuhi syarat "tiga 20" tetapi tidak akan mendapat barah paru-paru, sementara yang lain menghidap barah paru-paru. Secara genetik namakan perbezaan ini sebagai "kerentanan genetik".
Kerentanan barah paru-paru
Kerentanan genetik bermaksud bahawa disebabkan oleh pengaruh faktor genetik, atau kecacatan genetik tertentu, ia mempunyai ciri-ciri rentan terhadap penyakit tertentu. Seperti disebutkan di atas, ketika orang yang berbeza merokok dalam jumlah yang sama, beberapa orang menghidap barah paru-paru dan beberapa orang tidak menghidap barah paru-paru. Ini mungkin ditentukan oleh kerentanan genetik. Kerentanan genetik kanser paru-paru adalah satu lagi bidang penyelidikan kanser paru-paru yang penting. Walaupun sebilangan besar barah paru-paru tidak berkaitan dengan faktor genetik langsung kecuali beberapa barah paru-paru keluarga, melalui kaedah penyelidikan analisis hubungan genom, saintis telah menemui beberapa Gen dan lokus yang berkaitan dengan kerentanan genetik kanser paru-paru.
Keluarga sitokrom P450 adalah enzim metabolik oksidatif penting yang terlibat dalam metabolisme banyak ubat penting. Beberapa ahli keluarganya, CYP1A1, CYP1B1, CYP2D6, dan CYP2A13, mempunyai banyak laman web mengenai gen yang berkaitan dengan risiko barah paru-paru. Ini berkaitan dengan keupayaan metabolisme bahan kimia yang dibawa ke dalam badan seperti merokok dan pencemaran alam sekitar: orang yang mempunyai keupayaan metabolisme yang lemah mungkin lebih cenderung untuk mengumpulkan bahan seperti hidrokarbon aromatik poliklik (PAH), yang boleh menyebabkan kerosakan pada tisu paru-paru.
In addition, a cohort study of 5,739 patients with sporadic lung cancer and 5,848 healthy controls controlled the genetic susceptibility site at the rs2736100 (TERT) site on chromosome 5, and the TT genotype at this site was associated with a high incidence of lung cancer. TERT is a telomerase reverse transcriptase, under physiological conditions, it inhibits tumor production, but mutants may lose or reduce the function of the enzyme, thereby prone to tumors.
Sudah tentu, masih banyak kajian mengenai kerentanan genetik yang berkaitan dengan barah paru-paru, dan ini hanya beberapa. Dipercayai bahawa dengan penyelidikan yang lebih mendalam, lebih banyak gen kerentanan kanser paru-paru akan dikenal pasti, dan hubungan antara laman sensitif ini dan barah paru-paru akhirnya juga akan terungkap secara beransur-ansur.
Ubat tepat untuk barah paru-paru
“Precision medicine” is an emerging method of disease prevention and treatment, which is based on understanding the individual’s genes, environment and lifestyle. At present, precision medicine is the most mature, or the most effective, is barah paru-paru sel yang tidak kecil (NSCLC), which accounts for more than 80% of lung cancer. Surgery is still the most effective treatment, but it is only suitable for a small number of patients with non-localized metastases in NSCLC, and many patients will still relapse after surgery. In recent years, the role of epidermal growth factor receptor (EGFR) in the tumorigenesis of lung cancer and targeted therapy for EGFR are gradually being clinically recognized. Clinically reasonable screening of EGFR targeted therapy targets and determination of test results play an extremely important role in treatment The important role becomes the key to treatment. At the same time, KRAS and BRAF mutations and ALK gene rearrangement and the role of PD-L1 gene in lung cancer targeted therapy have also been gradually recognized clinically.
Egfr
Epidermal growth factor receptor (EGFR) and its family members play an important carcinogenic role by regulating cell proliferation, apoptosis, migration and tumor angiogenesis. Changes in EGFR signaling molecules involve the occurrence and development of various malignant tumors. Although the mechanism by which EGFR mutations cause cancer is not fully understood, it is clear that EGFR mutations can enhance tyrosine protein kinase activity.
Di Amerika Syarikat dan Asia, kira-kira 10% dan 35% pesakit dengan barah paru-paru sel bukan kecil mempunyai mutasi EGFR. Mutasi ini kebanyakannya berlaku pada ekson 18-21, di mana kira-kira 90% mutasi adalah penghapusan atau ekson ekson 19. Anak mutasi titik L21R 858. Mutasi ini meningkatkan aktiviti kinase EGFR, yang membawa kepada pengaktifan laluan isyarat hilir. Dalam kebanyakan kes, mutasi EGFR sering disertai dengan jenis mutasi atau penyusunan semula yang lain, seperti mutasi KRAS dan penyusunan semula ALK.
At present, the molecular targeted drugs developed for EGFR are mainly divided into two categories: 1. Small molecule tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib, and icotinib independently developed in China , The three can inhibit the activity of tyrosine kinase in EGFR intracellular domain; 2. Monoclonal antibody drugs (mAb), such as cetuximab and panitumumab, both of which bind to the extracellular domain of EGFR, blocking depends on EGFR activation of the ligand. The above drugs block EGFR-mediated intracellular signaling pathways through intracellular and extracellular pathways, respectively, thereby inhibiting tumor cell growth and migration, promoting tumor cell apoptosis, and increasing chemotherapy sensitivity.
CALAR
RAS is a common oncogene in human tumors. The genes associated with human tumors in the RAS gene family are composed of K-ras, H-ras and N-ras. Among them, K-ras (v-Ki-ras2 murine Kirsten sarkoma virus oncogene The highest mutation rate of homologues is 17-25%; at the same time, the K-ras gene is also the oncogenic gene with the highest mutation frequency in all tumors, and about 10-20% of tumors are related to the abnormal activation of K-ras. Can control the path of cell growth; when abnormal, it causes the cell to continue to grow and prevent apoptosis, which in turn leads to cancer.
Protein K-ras juga merupakan pengatur utama di hilir laluan isyarat EGFR. Setelah mutasi gen K-ras, ia selalu berada dalam keadaan aktif, sehingga tidak terpengaruh oleh isyarat hulu EGFR. Di negeri ini, rawatan dengan ubat yang disasarkan EGFR tidak sah. Kaedah mutasi karsinogenik yang paling biasa dalam gen K-ras adalah mutasi titik pada kodon 12, 13 dan 61 di terminal N, dan mutasi kodon 12 adalah yang paling biasa.
PAKAIAN
BRAF (toksin penapis sarkoma murine (v-raf) karsinogen homolog B1) adalah loka gen
hilir ke hilir KRAS di jalur isyarat EGFR dan mengekod protein serin / threonine kinase di jalur MAPK. Enzim mentransmisikan isyarat dari RAS ke MEK1 / 2, dan dengan demikian mengambil bahagian dalam mengatur pelbagai kejadian biologi di dalam sel.
Kumpulan penyelidik di dalam dan luar negara telah melaporkan bahawa BRAF mempunyai bahagian mutasi yang berbeza dalam barah paru-paru. Mutasi ini berlaku terutamanya di kawasan pengaktifan ekson 15, dan sekitar 92% daripadanya terletak pada nukleotida 1799 (mutasi T ke A), yang mengakibatkan penggantian asid glutamat (V600E) untuk valin yang dikodkan. Mutasi ini dapat menyebabkan pesakit mengembangkan daya tahan terhadap ubat antibodi seperti cetuximab.
Verofinil is a non-receptor tyrosine kinase inhibitor that selectively inhibits the BRAF protein located at the entrance of the MAPK / ERK pathway. Approved for the treatment of malignant melanoma, it is the first approved tyrosine kinase inhibitor for tumors carrying the BRAF (V600E mutation) gene. Clinical trials have shown that the drug has an effective rate of 42.9% for patients with this melanoma, but is basically ineffective for those who have not been mutated.
ALK
The ALK (anaplastic limfoma kinase) gene encodes a receptor tyrosine kinase and belongs to the insulin receptor superfamily. ALK proteins play an important role in brain development and can affect the nervous system of specific neurons. FDA approves ZYKADIA for patients with metastatic non-small cell lung cancer who have ALK positive progression or cannot use crizotinib, and crizotinib (XALKORI) is approved by the FDA for ALK positive non-small cell lung cancer patient. Rearranged ALK accounts for 5% of the incidence of NSCLC. In 2010, the New England Journal of Medicine reported that 82 of 1001 lung cancers were ALK-positive medications, with an effective rate of 60.8%. 347 patients with ALK positive (including platinum-based chemotherapy failure) randomized to receive crizotinib and chemotherapy significantly improved the proportion of tumor control.
Ujian klinikal telah menunjukkan bahawa setelah menggunakan ceritinib pada 180 pesakit dengan barah paru-paru sel kecil yang tidak menyatu ALK, 60% pesakit mengalami reaksi ubat yang berkesan, di mana 121 pesakit yang sebelumnya mendapat crizotinib mempunyai kadar tindak balas 55.4%, 59 pesakit yang belum mendapat rawatan mempunyai kadar tindak balas 69.5%. Gen PD-L1 PDCD1 (Progammed cell death1, PD1) mengkodekan imunoglobulin superfamily jenis I transmembran glycoprotein, yang dikaitkan dengan ligannya PD-L1, PD- Gabungan L2 mempunyai kesan penghambatan terhadap pengaktifan limfosit, memediasi negatif isyarat pengawalan tindak balas imun, dan mendorong apoptosis sel T anti-tumor. PD1 juga dapat mengawal sel T khusus antigen di kelenjar getah bening dengan mengatur gen Bcl-2. Pengumpulan. Ia memainkan peranan regulasi khusus dalam tumorigenesis, jangkitan virus dan penyakit autoimun. PD1 dan ligannya PD-L1 tergolong dalam molekul penggalak bersama keluarga B7. Molekul ini mempunyai profil ekspresi tisu yang luas dan ekspresi tinggi pada beberapa garis sel tumor. Banyak kajian menunjukkan bahawa ia berkaitan dengan mekanisme ketahanan kekebalan tumor. Jalur isyarat yang dimediasi oleh PD1 dan ligannya PD-L1 menjadi salah satu kaedah rawatan penyakit klinikal melalui intervensi imunologi.
PD-L1
Protein molecules are hardly expressed in normal tissues, but they are ubiquitous on the surface of human lung cancer, kanser ovari, colon cancer, renal cancer and melanoma. Studies have speculated that it can make tumor cells have the magical ability to escape immune response. . By inhibiting PD1 or PD-L1 to activate the anti-tumor activity of T cells and maintain its ability to detect and attack cancer cells, it can provide new ideas for cancer treatment. More than 200 patients with different types of tumors were enrolled in two different clinical trials. The largest cohort samples included melanoma and non-small cell lung cancer (NSCLC) patients. Both trials reported surprisingly long-lasting response rates (6–17% in the anti-PDL1 group and 18–28% in the anti-PD1 group), especially for melanoma patients (17% and 28% in both groups) , And the incidence of drug-related adverse events is also low (9% and 14% for grade 3 and 4 drug-related adverse events, respectively). More importantly, in the anti-PD1 group, the response rate of tumor patients with positive PD-L1 expression was 36%. It is worth noting that the trial purpose and sustained response rate of NSCLC patients also meet the trial requirements, and such patients are known for their resistance to imunoterapi. Ini adalah strategi imunoterapi yang paling berjaya bagi semua jenis tumor, dengan kadar tindak balas tumor berterusan sebanyak 10-15%.
As the concept of precision medicine continues to advance, the clinic has begun to use mutations to distinguish tumors rather than tissue sources. For example, if a gene mutation related to kanser payudara targeted medication is found in lung cancer, then this breast cancer medication may be used in the treatment of lung cancer; the National Cancer Institute (NCI) has initiated related clinical research (NCI-MATCH) . I believe that in the near future, this concept will be fully practiced in the clinic.
Pencegahan barah paru-paru
Untuk mencegah barah paru-paru secara ilmiah, selain menolak merokok aktif dan pasif, memperhatikan dan secara aktif merawat penyakit paru-paru kronik, mengurangkan pencemaran udara dalaman dan luaran, dan menjaga pengudaraan setelah pengudaraan, pemeriksaan perubatan secara berkala harus dilakukan setiap tahun. Populariti ini telah memainkan peranan penting dalam pengesanan awal kanser paru-paru. Bagi orang biasa, memahami latar belakang genetik mereka dan menyedari diri akan memberikan jaminan untuk kehidupan yang sihat.
