Masalah kanker 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 kanker 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.
Nyababkeun kanker paru
Anu jadi sabab utama kanker paru-paru kalebet ngaroko, polusi lingkungan, paparan padamelan, panyakit paru-paru kronis, sareng kerentanan genetik. Di antawisna, ngaroko mangrupikeun faktor résiko luhur anu munggaran pikeun kajadian kanker paru-paru. Langkung ti 80% kanker paru-paru dianggap disababkeun ku ngaroko, sareng perokok langkung ti 10 kali langkung kamungkinan ngembangkeun kanker paru-paru tibatan anu henteu ngaroko. Awéwé anu henteu ngaroko bakal ngagaduhan résiko kanker paru-paru 30% kusabab salakina ngaroko. Khususna, populasi "tilu 20", nyaéta, jalma anu ngaroko langkung ti 20 taun, jalma anu mimiti ngaroko sateuacan umur 20, sareng jalma anu ngaroko langkung ti 20 rokok sadinten mangrupikeun kelompok anu résiko luhur. pikeun kanker paru. Kusabab jumlah anu perokok pisan tinggi di India, insiden kanker paru di dieu kacida luhurna.
Faktor lingkungan sapertos ngaroko, paparan padamelan, sareng polusi lingkungan bakal ngagaduhan "pathogenisitas" anu béda pikeun jalma anu ngagaduhan latar genetik anu béda; contona, sababaraha urang patepung sareng kaayaan "tilu 20" tapi moal meunang kanker paru-paru, sedengkeun anu sanés ngagaduhan kanker paru-paru. Sacara genetik nelepon bédana ieu "kerentanan genetik".
Kerentanan kanker paru-paru
Karentanan genetik ngandung hartos kusabab pangaruh faktor genetik, atanapi cacat genetik tangtu, éta ngagaduhan ciri rentan ka panyakit-panyakit tinangtu. Sakumaha didadarkeun di luhur, nalika jalma anu béda ngaroko jumlah anu sami, sababaraha urang kanker kanker paru-paru sareng sababaraha urang henteu kaserang kanker paru-paru. Ieu bisa ditangtukeun ku karentanan genetik. Karentanan genetik kanker paru mangrupikeun bidang anu penting pikeun panilitian kanker paru-paru. Sanaos kaseueuran kanker paru henteu aya hubunganana sareng faktor genetik langsung kecuali sababaraha kangker paru-paru kulawarga, ngalangkungan metode panilitian analisis pakaitna génom, élmuwan mendakan sababaraha Gen sareng loci anu aya hubunganana sareng kerentanan genetik kanker paru-paru.
Kulawarga cytochrome P450 mangrupikeun énzim métabolik oksidatif anu penting dina metabolisme seueur ubar penting. Sababaraha anggota kulawargana, CYP1A1, CYP1B1, CYP2D6, sareng CYP2A13, gaduh sababaraha situs ngeunaan gén anu aya hubunganana sareng résiko kanker paru-paru. Ieu aya hubunganana sareng kapasitas metabolisme bahan kimia anu dibawa kana awak sapertos ngaroko sareng polutan lingkungan: jalma anu ngagaduhan kapasitas métabolik anu goréng panginten tiasa ngumpulkeun zat sapertos hidrokarbon aromatik polikliklikik (PAH), anu tiasa nyababkeun karusakan dina jaringan 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.
Tangtosna, masih seueur panilitian ngeunaan kerentanan genetik anu aya hubunganana sareng kanker paru-paru, sareng ieu aya sababaraha sababaraha. Dipercaya yén ku jero panilitian, langkung seueur gén karentanan kanker paru-paru bakal diidéntifikasi, sareng hubungan antara situs sénsitip ieu sareng kanker paru-paru akhirna ogé bakal laun diungkabkeun.
Obat presisi pikeun kanker 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 kanker paru sél non-leutik (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.
Endogna
Reséptor faktor pertumbuhan épidermal (EGFR) sareng anggota kulawargana maénkeun peran karsinogenik anu penting ku ngatur proliferasi sél, apoptosis, migrasi sareng angiogenesis tumor. Parobahan dina molekul sinyal EGFR ngalibatkeun lumangsungna sareng ngembangkeun rupa-rupa tumor ganas. Sanaos mékanisme mutasi EGFR nyababkeun kanker teu acan kahartos, jelas yén mutasi EGFR tiasa ningkatkeun kagiatan kinase protéin tirosin.
Di Amérika Serikat sareng Asia, sakitar 10% sareng 35% pasien sareng kanker paru-paru sél alit henteu gaduh mutasi EGFR. Mutasi ieu seuseueurna kajantenan dina exons 18-21, anu sakitar 90% mutasi mangrupikeun exon 19 hapusan atanapi ekson. Putra 21 L858R titik mutasi. Mutasi ieu ningkatkeun kagiatan kinase EGFR, ngarah kana aktivasina jalur sinyalna hilir. Dina kaseueuran kasus, mutasi EGFR sering dibarengan ku jinis mutasi atanapi panyusunan anu sanés, sapertos mutasi KRAS sareng pangaturan ulang ALK.
Ayeuna, ubar sasaran molekular dikembangkeun pikeun EGFR utamana dibagi kana dua kategori: 1. Sambetan tirosin kinase molekul leutik (TKI), sapertos gefitinib sareng erlotinib, sareng icotinib sacara mandiri dikembangkeun di Cina, Tilu tiasa ngahambat kagiatan tirosin kinase. dina domain intrasélular EGFR; 2. Obat antibodi monoklonal (mAb), sapertos cetuximab sareng panitumumab, duanana ngabeungkeut kana domain ekstrasélular EGFR, meungpeuk gumantung kana aktivasina EGFR tina ligan. Ubar di luhur meungpeuk jalur sinyal intrasélular anu dimédiasi EGFR ngaliwatan jalur intrasélular sareng ekstrasélular masing-masing, sahingga ngahambat pertumbuhan sél tumor sareng migrasi, ngamajukeun apoptosis sél tumor, sareng ningkatkeun sensitipitas kémoterapi.
KRAS
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.
Protéin K-ras ogé régulator konci dina hilir jalur sinyal EGFR. Saatos mutasi gén K-ras, éta teras-terasan dina kaayaan anu diaktipkeun, janten henteu kapangaruhan ku sinyal hulu EGFR. Dina kaayaan ieu, pangobatan kalayan ubar anu ditargétkeun EGFR henteu valid. Cara mutasi karsinogenik anu paling umum dina gén K-ras nyaéta mutasi titik dina codons 12, 13 sareng 61 di N-terminus, sareng mutasi codon 12 anu paling umum.
BARAYA
BRAF (murine sarcoma filter toksin (v-raf) karsinogen homolog B1) mangrupikeun gén
ted hilir KRAS dina jalur sinyal EGFR sareng ngodekeun sérin / protéin théonin kinase dina jalur MAPK. Énzim ngirimkeun sinyal ti RAS ka MEK1 / 2, sahingga ngiringan ngatur sababaraha rupa kajadian biologis dina sél.
Grup panilitian di bumi sareng luar negeri ngalaporkeun yén BRAF ngagaduhan babandingan mutasi anu béda dina kanker paru-paru. Mutasi ieu biasana kajantenan di daérah aktivasina of exon 15, sareng sakitar 92% di antawisna aya di nukléotida 1799 (T mutasi ka A), hasilna substitusi asam glutamat (V600E) pikeun valin anu dikodekeun. Mutasi ieu tiasa nyababkeun penderita ngembangkeun résistansi kana ubar antibodi sapertos 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 lymphoma 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.
Percobaan klinis nunjukkeun yén saatos nganggo ceritinib di 180 penderita kanker paru sél sanés alit-alit, 60% pasien ngagaduhan réaksi ubar anu épéktip, dimana 121 pasién anu saacanna nampi crizotinib ngagaduhan tingkat réspon 55.4%, 59 pasién anu henteu nampi perlakuan naon-naon gaduh tingkat réspon 69.5%. PD-L1 PDCD1 (gén sél Patied1, PD1) gén nyandikeun tipe superfamily imunoglobulin tipe I transmembrane glikoprotein, anu aya hubunganana sareng ligan PD-L1, PD- Kombinasi L2 ngagaduhan pangaruh anu ngahambat kana aktivasina limfosit, ngégél négatip sinyal pangaturan réspon imunitas, sareng nyababkeun apoptosis sél anti anti tumor T. PD1 ogé tiasa ngendalikeun sél T spésifik antigen dina titik limfa ku ngatur gén Bcl-2. Akumulasi. Éta maénkeun peran pangaturan khusus pikeun tumigenesis, inféksi virus sareng panyakit otoimun. PD1 sareng ligan PD-L1 na kagolong kana molekul ko-stimulasi kulawarga B7. Molekul ieu ngagaduhan profil éksprési jaringan anu lega sareng éksprési tinggi dina sababaraha garis sél tumor. Seueur panilitian parantos nunjukkeun yén éta aya hubunganana sareng mékanisme kabur imun tina tumor. Jalur sinyal anu dimédiasi ku PD1 sareng ligan PD-L1 na janten salah sahiji metode pangobatan panyakit klinis ngalangkungan intervensi imunologis.
Pd-l1
Protein molecules are hardly expressed in normal tissues, but they are ubiquitous on the surface of human lung cancer, kanker indung, 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 immunotherapy. Ieu mangrupikeun strategi imunoterapi anu paling suksés pikeun sadaya jinis tumor, kalayan tingkat réspon tumor anu pengkuh 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 kanker 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 kanker paru
Pikeun nyegah kanker paru-paru sacara ilmiah, salian ti nolak ngaroko aktif sareng pasif, merhatoskeun sareng sacara aktif ngubaran panyakit paru-paru kronis, ngirangan polusi udara di jero ruangan sareng di luar ruangan, sareng ngajaga ventilasi saatos dihirupkeun, pamariksaan médis rutin kedah dilaksanakeun unggal taun. Popularitas ieu parantos maénkeun peran penting dina deteksi awal kanker paru-paru. Pikeun jalma biasa, paham kana kasang tukang genetikna sareng sadar ku dirina bakal masihan jaminan pikeun kahirupan anu séhat.
