O'pka saratoni muammosi
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 o'pka saratoni 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.
O'pka saratonining sabablari
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.
Chekish, kasbga ta'sir qilish va atrof-muhitning ifloslanishi kabi atrof-muhit omillari turli xil genetik kelib chiqishi bo'lgan odamlar uchun har xil "patogenlik" ga ega bo'ladi; Masalan, ba'zi odamlar "uchta 20" shartlarini bajaradilar, ammo o'pka saratoniga duchor bo'lmaydilar, boshqalari o'pka saratoniga chalinadi. Ushbu farqni genetik jihatdan "genetik sezuvchanlik" deb atashadi.
O'pka saratoniga moyilligi
Genetik sezuvchanlik degani, irsiy omillarning ta'siri yoki ma'lum bir irsiy nuqson tufayli u ma'lum kasalliklarga moyil bo'lish xususiyatlariga ega. Yuqorida ta'kidlab o'tilganidek, turli xil odamlar bir xil miqdordagi chekishganda, ba'zi odamlar o'pka saratoniga chalinadi, ba'zilari esa o'pka saratoniga chalinmaydi. Bu genetik sezuvchanlik bilan aniqlanishi mumkin. O'pka saratonining genetik ta'sirchanligi o'pka saratoni tadqiqotlarining yana bir muhim yo'nalishi hisoblanadi. Garchi o'pka saratonining ko'p qismi to'g'ridan-to'g'ri genetik omillar bilan bog'liq bo'lmasa-da, ayrim oilaviy o'pka saratonidan tashqari, genom bo'yicha assotsiatsiya tahlilining tadqiqot usullari orqali olimlar o'pka saratoniga genetik ta'sirchanligi bilan bog'liq ba'zi genlar va lokuslarni topdilar.
Sitoxrom P450 oilasi ko'plab muhim dorilar almashinuvida ishtirok etadigan muhim oksidlovchi metabolik ferment hisoblanadi. Uning oilasining bir nechta a'zolari, CYP1A1, CYP1B1, CYP2D6 va CYP2A13, o'pka saratoni xavfi bilan bog'liq bo'lgan genlarda bir nechta joylarga ega. Bu chekish va atrof-muhitni ifloslantiruvchi moddalar kabi tanaga olib kiriladigan kimyoviy moddalarning metabolizm qobiliyati bilan bog'liq: metabolizm qobiliyati past odamlar o'pka to'qimalariga zarar etkazishi mumkin bo'lgan politsiklik aromatik uglevodorodlar (PAH) kabi moddalarni to'plashlari mumkin.
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 shish production, but mutants may lose or reduce the function of the enzyme, thereby prone to tumors.
Albatta, o'pka saratoni bilan bog'liq genetik sezuvchanlik bo'yicha hali ko'p tadqiqotlar mavjud va bularning ba'zilari. Tadqiqotlarning chuqurlashishi bilan o'pka saratoniga ko'proq moyil bo'lish genlari aniqlanadi va bu sezgir joylar bilan o'pka saratoni o'rtasidagi munosabatlar ham asta-sekin aniqlanadi deb ishoniladi.
O'pka saratoni uchun aniq dori
“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 kichik hujayrali o'pka saratoni (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.
Amerika Qo'shma Shtatlari va Osiyoda kichik hujayrali bo'lmagan o'pka saratoni bilan kasallangan bemorlarning taxminan 10% va 35% EGFR mutatsiyasiga ega. Ushbu mutatsiyalar asosan 18-21-sonli ekzonlarda uchraydi, shundan mutatsiyalarning 90% ga yaqini ekson 19-chi o'chirish yoki ekzonlardir. O'g'il 21 L858R nuqta mutatsiyasi. Ushbu mutatsiyalar EGFR kinaz faolligini oshirib, quyi oqim signalizatsiya yo'llarining faollashishiga olib keladi. Ko'pgina hollarda, EGFR mutatsiyalari ko'pincha boshqa turdagi mutatsiyalar yoki qayta tashkil etish bilan birga keladi, masalan, KRAS mutatsiyalari va ALKni qayta tashkil etish.
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.
SCRATCH
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.
K-ras oqsili, shuningdek, EGFR signalizatsiya yo'lining pastki qismida asosiy regulyator hisoblanadi. K-ras genining mutatsiyasidan so'ng u har doim faol holatidadir, shuning uchun unga EGFR ning yuqori oqimi signali ta'sir qilmaydi. Bunday holatda EGFR maqsadli dorilar bilan davolash bekor hisoblanadi. K-ras genidagi kanserogen mutatsiyalarning eng keng tarqalgan usuli bu N-terminalidagi 12, 13 va 61 kodonlaridagi nuqta mutatsiyalari va 12-kodon mutatsiyalari eng keng tarqalgan.
AKA
BRAF (murin sarkomasi filtri toksini (v-raf) kanserogen homolog B1) gen lokusidir.
EGFR signalizatsiya yo'lidagi KRASning quyi oqimida va MAPK yo'lidagi serin / treonin oqsil kinazasini kodlaydi. Ferment signalni RASdan MEK1 / 2 ga o'tkazadi va shu bilan hujayradagi turli xil biologik hodisalarni boshqarishda ishtirok etadi.
Uyda va chet elda olib borilgan tadqiqot guruhlari BRAFning o'pka saratonida mutatsiyalarning har xil nisbati borligini xabar qilishdi. Ushbu mutatsiyalar asosan ekzon 15 ning faollashish mintaqasida sodir bo'lgan va ularning taxminan 92% nukleotid 1799 da joylashgan (T dan mutatsiyaga), natijada glutamik kislota (V600E) kodlangan valin bilan almashtirilgan. Ushbu mutatsiya bemorlarda setuksimab kabi antikor dorilariga qarshilik ko'rsatishiga olib kelishi mumkin.
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.
Klinik tadkikotlar shuni ko'rsatdiki, ALK bilan birlashtirilgan kichik hujayrali bo'lmagan o'pka saratoniga chalingan 180 bemorda seritinib qo'llangandan so'ng, bemorlarning 60 foizida samarali dori reaktsiyalari bo'lgan, shulardan ilgari krizotinib olgan 121 bemorning javob darajasi 55.4%, 59 hech qanday davolanmagan bemorlarning javob darajasi 69.5% ni tashkil qiladi. PD-L1 PDCD1 (Progammed cell death1, PD1) geni uning ligandlari PD-L1, PD bilan bog'langan immunoglobulin superfamil tip I transmembran glikoproteinni kodlaydi, L- L2 birikmasi limfotsitlarning faollashishiga to'sqinlik qiladi, manfiy vositachilik qiladi. immunitet reaktsiyasini tartibga soluvchi signal va o'smalarga qarshi T hujayralarining apoptozini keltirib chiqaradi. PD1 Bcl-2 genini tartibga solish orqali limfa tugunlarida antigenga xos T hujayralarini ham boshqarishi mumkin. Yig'ish. U shish paydo bo'lishi, virusli infektsiyalar va otoimmun kasalliklarda o'ziga xos tartibga soluvchi rol o'ynaydi. PD1 va uning ligand PD-L1 B7 oilasining ko-stimulyatorli molekulasiga tegishli. Ushbu molekula to'qimalarning ekspression profiliga va ba'zi o'sma hujayralari satrlarida yuqori ekspressionga ega. Ko'pgina tadqiqotlar shuni ko'rsatdiki, bu o'smalarning immunitetli qochish mexanizmi bilan bog'liq. PD1 va uning ligand PD-L1 vositachiligidagi signalizatsiya yo'li immunologik aralashuv orqali kasallikni klinik davolash usullaridan biriga aylanmoqda.
PD-L1
Protein molecules are hardly expressed in normal tissues, but they are ubiquitous on the surface of human lung cancer, ovaryan saraton, 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 immunoterapiya. Bu barcha turdagi o'smalar uchun eng muvaffaqiyatli immunoterapiya strategiyasi bo'lib, o'simtaning barqaror javob darajasi 10-15% ni tashkil qiladi.
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 ko'krak saratoni 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.
O'pka saratonining oldini olish
O'pka saratonini ilmiy jihatdan oldini olish uchun faol va passiv chekishni rad etish, o'pkaning surunkali kasalliklariga e'tibor berish va faol davolash, ichki va tashqi havoning ifloslanishini kamaytirish, ventilyatsiyadan keyin ventilyatsiyani saqlash bilan bir qatorda har yili tibbiy ko'riklar o'tkazilishi kerak. Buning mashhurligi o'pka saratonini erta aniqlashda muhim rol o'ynadi. Oddiy odamlar uchun ularning genetik kelib chiqishini tushunish va o'z-o'zini anglash sog'lom hayot uchun kafolat beradi.
