Longkanker probleem
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 Long kanker 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.
Oorsake van longkanker
Die hoofoorsake van longkanker sluit in rook, omgewingsbesoedeling, beroepsblootstelling, chroniese longsiekte en genetiese vatbaarheid. Onder hulle is rook die eerste hoërisikofaktor vir die voorkoms van longkanker. Meer as 80% van longkanker word beskou as veroorsaak deur rook, en rokers is meer as 10 keer meer geneig om longkanker te ontwikkel as nie-rokers. Vroue wat nie rook nie, sal 'n 30% verhoogde risiko van longkanker hê omdat hul man rook. Veral die "drie 20" bevolking, dit wil sê mense wat al meer as 20 jaar gerook het, mense wat voor die ouderdom van 20 begin rook het, en mense wat meer as 20 sigarette per dag rook, is almal hoërisikogroepe vir longkanker. As gevolg van die baie hoë aantal rokers in Indië, is die voorkoms van longkanker hier baie hoog.
Omgewingsfaktore soos rook, beroepsblootstelling en omgewingsbesoedeling sal verskillende "patogenisiteit" hê vir mense met verskillende genetiese agtergronde; byvoorbeeld, sommige mense voldoen aan die "drie 20" voorwaardes, maar sal nie longkanker kry nie, terwyl ander longkanker gekry het. Geneties noem hierdie verskil "genetiese vatbaarheid".
Longkanker vatbaarheid
Genetiese vatbaarheid beteken dat dit as gevolg van die invloed van genetiese faktore, of 'n sekere genetiese defek, die eienskappe het dat dit geneig is tot sekere siektes. Soos hierbo genoem, wanneer verskillende mense dieselfde hoeveelheid rook, ontwikkel sommige mense longkanker en sommige mense ontwikkel nie longkanker nie. Dit kan bepaal word deur genetiese vatbaarheid. Die genetiese vatbaarheid van longkanker is nog 'n belangrike veld van longkankernavorsing. Alhoewel die meeste van die longkankers nie verwant is aan direkte genetiese faktore nie, behalwe vir sommige familiale longkankers, het wetenskaplikes deur die navorsingsmetodes van genoomwye assosiasie-analise sommige gene en lokusse gevind wat verband hou met die genetiese vatbaarheid van longkanker.
Die sitochroom P450-familie is 'n belangrike oksidatiewe metaboliese ensiem wat betrokke is by die metabolisme van baie belangrike middels. Verskeie lede van sy familie, CYP1A1, CYP1B1, CYP2D6 en CYP2A13, het verskeie plekke op gene wat geassosieer word met die risiko van longkanker. Dit hou verband met die metaboliese kapasiteit van chemikalieë wat in die liggaam ingebring word, soos rook en omgewingsbesoedelende stowwe: mense met swak metaboliese kapasiteit kan meer geneig wees om stowwe soos polisikliese aromatiese koolwaterstowwe (PAK) op te bou, wat skade aan longweefsel kan veroorsaak.
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.
Natuurlik is daar nog baie studies oor genetiese vatbaarheid wat verband hou met longkanker, en hier is net 'n paar. Daar word geglo dat met die verdieping van navorsing meer longkanker vatbaarheidsgene geïdentifiseer sal word, en die verband tussen hierdie sensitiewe plekke en die uiteindelike longkanker sal ook geleidelik aan die lig gebring word.
Presisie medisyne vir longkanker
“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 longkanker wat nie klein is nie (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
Epidermale groeifaktorreseptor (EGFR) en sy familielede speel 'n belangrike karsinogeniese rol deur selproliferasie, apoptose, migrasie en tumorangiogenese te reguleer. Veranderinge in EGFR seinmolekules behels die voorkoms en ontwikkeling van verskeie kwaadaardige gewasse. Alhoewel die meganisme waardeur EGFR-mutasies kanker veroorsaak nie ten volle verstaan word nie, is dit duidelik dat EGFR-mutasies tyrosienproteïenkinase-aktiwiteit kan verbeter.
In die Verenigde State en Asië het ongeveer 10% en 35% van pasiënte met nie-kleinselle longkanker EGFR-mutasies. Hierdie mutasies kom meestal in eksons 18-21 voor, waarvan ongeveer 90% van mutasies ekson 19 delesies of eksons is. Seun 21 L858R puntmutasie. Hierdie mutasies verhoog EGFR kinase aktiwiteit, wat lei tot die aktivering van stroomaf sein paaie. In die meeste gevalle gaan EGFR-mutasies dikwels gepaard met ander tipes mutasies of herrangskikkings, soos KRAS-mutasies en ALK-herrangskikkings.
Tans word die molekulêre geteikende middels wat vir EGFR ontwikkel is hoofsaaklik in twee kategorieë verdeel: 1. Klein molekule tyrosienkinase inhibeerders (TKI), soos gefitinib en erlotinib, en icotinib onafhanklik ontwikkel in China. Die drie kan die aktiwiteit van tyrosine kinase inhibeer in EGFR intrasellulêre domein; 2. Monoklonale teenliggaampies (mAb), soos cetuximab en panitumumab, wat albei aan die ekstrasellulêre domein van EGFR bind, blokkering hang af van EGFR-aktivering van die ligand. Bogenoemde middels blokkeer EGFR-gemedieerde intrasellulêre seinweë deur onderskeidelik intrasellulêre en ekstrasellulêre weë, waardeur tumorselgroei en -migrasie inhibeer, tumorsel-apoptose bevorder en chemoterapie-sensitiwiteit verhoog word.
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 sarkoom 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-proteïen is ook 'n sleutelreguleerder in die stroomaf van die EGFR-seinweg. Na mutasie van die K-ras-geen is dit altyd in 'n geaktiveerde toestand, dus word dit nie deur die stroomop sein van EGFR beïnvloed nie. In hierdie toestand is behandeling met EGFR-geteikende middels ongeldig. Die mees algemene manier van karsinogene mutasies in die K-ras geen is puntmutasies by kodons 12, 13 en 61 by die N-terminus, en kodon 12 mutasies is die algemeenste.
BROER
BRAF (muriene sarkoom filter toksien (v-raf) karsinogeen homoloog B1) is 'n geen loka
stroomaf van KRAS in die EGFR-seinweg en kodeer die serien/treonien-proteïenkinase in die MAPK-weg. Die ensiem transduseer die sein van RAS na MEK1 / 2, en neem dus deel aan die regulering van verskeie biologiese gebeurtenisse in die sel.
Navorsingsgroepe by die huis en in die buiteland het berig dat BRAF verskillende proporsies van mutasies in longkanker het. Hierdie mutasies het hoofsaaklik in die aktiveringsgebied van ekson 15 voorgekom, en ongeveer 92% van hulle was geleë by nukleotied 1799 (T-mutasie na A), wat gelei het tot die vervanging van glutamiensuur (V600E) vir die gekodeerde valien. Hierdie mutasie kan veroorsaak dat pasiënte weerstand teen teenliggaammiddels soos cetuximab ontwikkel.
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 melanoom, 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 limfoom 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.
Kliniese proewe het getoon dat na die gebruik van ceritinib by 180 pasiënte met ALK-gefuseerde nie-kleinselle longkanker, 60% van die pasiënte effektiewe geneesmiddelreaksies gehad het, waarvan 121 pasiënte wat voorheen crizotinib ontvang het 'n responskoers van 55.4% gehad het, 59 pasiënte wat geen behandeling ontvang het nie, het 'n responskoers van 69.5%. PD-L1 PDCD1 (Progammed cell death1, PD1) geen kodeer 'n immunoglobulien superfamilie tipe I transmembraan glikoproteïen, wat geassosieer word met sy ligande PD-L1, PD- Die kombinasie van L2 het 'n inhiberende effek op die aktivering van limfosiete, bemiddel die negatiewe regulatoriese sein van die immuunrespons, en induseer die apoptose van anti-tumor T-selle. PD1 kan ook die antigeen-spesifieke T-selle in limfknope beheer deur die Bcl-2-geen te reguleer. Akkumulasie. Dit speel 'n spesifieke regulerende rol in tumorgenese, virusinfeksies en outo-immuun siektes. PD1 en sy ligand PD-L1 behoort tot die ko-stimulerende molekule van die B7-familie. Hierdie molekule het 'n wye weefseluitdrukkingprofiel en hoë uitdrukking op sommige tumorsellyne. Baie studies het getoon dat dit verband hou met die immuun ontsnappingsmeganisme van gewasse. Die seinweg wat deur PD1 en sy ligand PD-L1 bemiddel word, word een van die metodes van kliniese siektebehandeling deur immunologiese intervensie.
PD-L1
Protein molecules are hardly expressed in normal tissues, but they are ubiquitous on the surface of human lung cancer, eierstokkanker, 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 immunotherapie. This is by far the most successful immunotherapy strategy of all types of tumors, with a persistent tumor response rate of 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 borskanker 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.
Voorkoming van longkanker
Om longkanker wetenskaplik te voorkom, behalwe om aktiewe en passiewe rook te weier, aandag te gee aan en aktief te behandel chroniese longsiektes, die vermindering van binne- en buitelugbesoedeling en die handhawing van ventilasie na ventilasie, moet gereelde mediese ondersoeke elke jaar uitgevoer word. Die gewildheid hiervan het 'n belangrike rol gespeel in die vroeë opsporing van longkanker. Vir gewone mense sal die begrip van hul genetiese agtergrond en selfbewus wees 'n waarborg vir 'n gesonde lewe bied.
