MH_dev_105

X-ray cross-complementing group 1 and thymidylate synthase polymorphisms might predict response to chemoradiotherapy in rectal cancer patients . PURPOSE : DB00544 MEN - based chemoradiotherapy before total mesorectal excision is currently the standard treatment of Stage II and III rectal cancer patients . We used known predictive pharmacogenetic biomarkers to identify the responders to preoperative chemoradiotherapy in our series . METHODS AND MATERIALS : A total of 93 Stage II-III rectal cancer patients were genotyped using peripheral blood samples . The genes analyzed were X-ray cross-complementing group 1 ( P18887 REA ) , P07992 REA , P42898 REA , P00533 REA , Q12882 REA , and P04818 REA . The patients were treated with 225 mg / m ( 2 ) / d continuous infusion of 5 - fluorouracil concomitantly with radiotherapy ( 50.4 Gy ) followed by total mesorectal excision . The outcomes were measured by tumor regression grade ( TRG ) as a major response ( TRG 1 and TRG 2 ) or as a poor response ( Q9Y512 REA , TRG 4 , and TRG 5 ) . RESULTS : The major histopathologic response rate was 47.3 % . P18887 REA G / G carriers had a greater probability of response than G / A carriers ( odds ratio , 4.18 ; 95 % confidence interval , 1.62- 10.74 , p = . 003 ) Patients with polymorphisms associated with high expression of thymidylate synthase ( 2R / 3G , 3C / 3G , and 3G / 3G ) showed a greater pathologic response rate compared with carriers of low expression ( odds ratio , 2.65 ; 95 % confidence interval , 1.10- 6.39 , p = . 02 ) No significant differences were seen in the response according to P00533 REA , P07992 REA , MTHFR_C 677 and MTHFR_A 1298 expression . CONCLUSIONS : P18887 REA G / G and thymidylate synthase ( 2R / 3G , 3C / 3G , and 3G / 3G ) are independent factors of a major response . Germline thymidylate synthase and P18887 REA polymorphisms might be useful as predictive markers of rectal tumor response to neoadjuvant chemoradiotherapy with 5 - fluorouracil .

Phase II trial of weekly alternating sequential BIBF 1120 and afatinib for advanced colorectal cancer . AIM : The feasibility of an alternating regimen of BIBF 1120 , a potent , oral , triple angiokinase inhibitor , and afatinib ( DB08916 SUB ) , a potent ErbB family blocker , was explored in patients with advanced pretreated colorectal cancer ( CRC ) . PATIENTS AND METHODS : Patients received repeated courses of alternating 7 - day treatment periods , first with BIBF 1120 250 mg twice daily and then afatinib 50 mg once daily . The primary endpoint was the objective response rate ; the incidence / severity of adverse events ( AEs ) and pharmacokinetics ( PK ) were determined . RESULTS : Forty-six patients ( ≥ 4 prior lines , most anti - P15692 REA and / or - P00533 REA pretreated ) received BIBF 1120 and afatinib . No objective responses were observed ; the best response was stable disease in 20 patients ( 43.5 % ) . Seven patients ( 15.2 % ) remained progression-free for ≥ 16 weeks . Median progression-free survival was 1.9 months ; median overall survival was 5.5 months . The most frequent drug-related AEs were diarrhoea ( 80.4 % ) , asthenia ( 47.8 % ) , nausea ( 43.5 % ) and rash ( 41.3 % ) . PK assessments did not show obvious alterations for either drug . CONCLUSION : Weekly alternating administration of BIBF 1120 and afatinib is feasible ; however , its efficacy was limited in this highly palliative patient population .

Convergent and divergent cellular responses by ErbB 4 isoforms in mammary epithelial cells . Associations of ErbB 4 ( Q15303 REA / Q15303 REA ) , the fourth member of the P00533 REA family , with cancer are variable , possibly as a result of structural diversity of this receptor . There are multiple structural isoforms of Q15303 REA arising by alternative mRNA splicing , and a subset undergo proteolysis that releases membrane-anchored and soluble isoforms that associate with transcription factors and coregulators to modulate transcription . To compare the differential and common signaling activities of full-length ( FL ) and soluble intracellular isoforms of Q15303 REA , four JM-a isoforms ( FL and soluble intracellular domain ( ICD ) CYT - 1 and CYT - 2 ) were expressed in isogenic MCF 10A cells and their biologic activities were analyzed . Both FL and ICD CYT - 2 promoted cell proliferation and invasion , and CYT - 1 suppressed cell growth . Transcriptional profiling revealed several new and underexplored Q15303 REA - regulated transcripts , including : proteases / protease inhibitors ( P08254 REA and P07093 REA ) , the YAP / Hippo pathway ( P29279 REA , O00622 REA , and P09486 REA ) , the mevalonate / cholesterol pathway ( P04035 REA , Q01581 REA , P01130 REA , and Q9UBM7 ) , and cytokines ( P10145 REA , P78556 REA , and P09341 REA ) . Many of these transcripts were subsequently validated in a luminal breast cancer cell line that normally expresses Q15303 REA . Furthermore , ChIP-seq experiments identified O75689 REA , P02649 REA , P09486 REA , P16949 REA , and Q05195 as novel molecular targets of Q15303 REA . These findings clarify the diverse biologic activities of Q15303 REA isoforms , and reveal new and divergent functions . IMPLICATIONS : ErbB 4 as a regulator of Hippo and mevalonate pathways provides new insight into milk production and anabolic processes in normal mammary epithelia and cancer .

Dermatologic adverse events associated with afatinib : an oral ErbB family blocker . Dermatologic adverse events ( AEs ) are frequently observed in patients receiving P01133 REA receptor ( P00533 REA ; also known as ErbB 1 ) tyrosine kinase inhibitor therapy . The impact of these AEs goes beyond cosmesis to the discomfort from itching , pain and secondary infections , all of which may significantly impact on patient well-being , adherence and clinical outcomes . DB08916 SUB is a potent , irreversible , oral , ErbB family blocker , inhibiting P00533 REA ( ErbB 1 ) , P04626 REA ( ErbB 2 ) and ErbB 4 receptor kinases . It also inhibits transphosphorylation of ErbB 3 . Similar to P00533 REA inhibitors , dermatologic AEs have been frequently observed in patients treated with afatinib . Papulopustular ( acneiform ) rash , pruritus , xerosis , paronychia and alopecia will require patient education and proactive treatment interventions . This article summarizes current data on the dermatologic AEs associated with afatinib treatment across the clinical trial program , and provides strategies for their effective management .

P00533 REA inhibitors in non-small cell lung cancer ( NSCLC ) : the emerging role of the dual irreversible P00533 REA / P04626 REA inhibitor DB08916 SUB . Non-small cell lung cancer ( NSCLC ) is one of the most lethal types of cancer and is associated with significant mortality and morbidity worldwide . Despite improvements in conventional treatment for NSCLC , survival remains poor and improvements in patient outcome are warranted . Over recent years , basic scientific research has dramatically increased our knowledge of the pathogenesis of lung cancer and allowed us to uncover and understand the cellular pathways involved in this process . This has led to the development of therapies to selectively target these pathways . Among these , the epidermal growth factor receptor ( P00533 REA ) tyrosine kinase family and related downstream pathways play a critical role in cancer development and over recent years have become a validated target in NSCLC . The development of monoclonal antibodies and first-generation tyrosine kinase inhibitors ( TKIs ) targeted towards P00533 REA has had a considerable impact on patient outcomes . However , despite dramatic and sustained responses and the discovery of specific patient subgroups that may derive clinical benefit , resistance to first-generation P00533 REA TKIs inevitably develops . A new generation of agents have been developed to provide superior potency of target inhibition and further individualize the treatment of NSCLC . This article reviews P00533 REA - targeted therapies currently available for use and undergoing clinical development for the treatment of NSCLC , specifically focusing on next generation agents including DB08916 SUB , an irreversible dual inhibitor of P00533 REA and P04626 REA kinases .

Ventilation-induced increases in P00533 REA ligand mRNA are not altered by intra-amniotic LPS or ureaplasma in preterm lambs . Chorioamnionitis and mechanical ventilation are associated with bronchopulmonary dysplasia ( BPD ) in preterm infants . Mechanical ventilation at birth activates both inflammatory and acute phase responses . These responses can be partially modulated by previous exposure to intra-amniotic ( IA ) LPS or Ureaplasma parvum ( UP ) . P00533 REA ( P00533 REA ) ligands participate in lung development , and angiotensin converting enzyme ( P12821 REA ) 1 and Q9BYF1 contribute to lung inflammation . We asked whether brief mechanical ventilation at birth altered P00533 REA and P12821 REA pathways and if antenatal exposure to IA LPS or UP could modulate these effects . Ewes were exposed to IA injections of UP , LPS or saline multiple days prior to preterm delivery at 85 % gestation . Lambs were either immediately euthanized or mechanically ventilated for 2 to 3 hr . IA UP and LPS cause modest changes in the P00533 REA ligands amphiregulin ( P15514 REA ) , epiregulin ( O14944 REA ) , heparin binding epidermal growth factor ( HB - P01133 REA ) , and betacellulin ( P35070 REA ) mRNA expression . Mechanical ventilation greatly increased mRNA expression of P15514 REA , O14944 REA , and HB - P01133 REA , with no additional increases resulting from IA LPS or UP . With ventilation P15514 REA and O14944 REA mRNA localized to cells in terminal airspace . P00533 REA mRNA also increased with mechanical ventilation . IA UP and LPS decreased ACE 1 mRNA and increased Q9BYF1 mRNA , resulting in a 4 fold change in the ACE 1 / Q9BYF1 ratio . Mechanical ventilation with large tidal volumes increased both ACE 1 and Q9BYF1 expression . The alterations seen in P12821 REA with IA exposures and P00533 REA pathways with mechanical ventilation may contribute to the development of BPD in preterm infants .

The LUX-Lung clinical trial program of afatinib for non-small-cell lung cancer . P00533 REA ( P00533 REA ) - mutant non-small-cell lung cancer ( NSCLC ) represents a distinct disease entity whose molecular phenotype predicts exquisite sensitivity to the reversible P00533 REA - tyrosine kinase inhibitors ( TKIs ) gefitinib or erlotinib . However , primary or acquired resistance to these agents remains a major clinical problem . DB08916 SUB is a novel dual irreversible P00533 REA / P04626 REA TKI that has been shown in preclinical studies to potentially prevent , delay or overcome resistance to reversible P00533 REA - TKIs . On this basis , the LUX-Lung clinical trial program has been recently launched for testing this molecule in advanced NSCLC patients . Notably , early results from the randomized LUX-Lung 1 trial indicate that afatinib significantly prolongs progression-free survival compared with placebo in pretreated patients with clinically acquired resistance to gefitinib or erlotinib . On the other hand , the LUX-Lung 2 trial shows that afatinib is highly active in the P00533 REA - mutant subgroup of patients . While these preliminary data open a new exciting scenario for the future development of anti - P00533 REA therapies in NSCLC , ongoing afatinib trials will definitively establish a role for this molecule in the treatment of advanced NSCLC .

DB08916 SUB and its encapsulated polymeric micelles inhibits P04626 REA - overexpressed colorectal tumor cell growth in vitro and in vivo . Colorectal cancer ( CRC ) is known as a common malignant neoplasm worldwide . The role of P00533 REA / P04626 REA in CRC is unclear . DB08916 SUB is an irreversible P00533 REA / P04626 REA inhibitor . There were few studies of afatinib on CRC . Here , we investigated the protein levels / expressions of P04626 REA in sera and tumors from CRC patients and the therapeutic effect of afatinib on P04626 REA - overexpressed CRC in vitro and in vivo . The increased P04626 REA levels were detected in the collected sera and tumors of patients with CRC . The serological P04626 REA levels were correlated with the tumor P04626 REA expressions in patients . DB08916 SUB also inhibited the P04626 REA - positive tumor cell growth and caused apoptosis in P04626 REA - overexpressed human colorectal cancer HCT - 15 cells but not in low P04626 REA expressed human gastric cancer MKN 45 cells . In vivo study showed that afatinib reduced tumor growth in P04626 REA - overexpressed xenografts . Moreover , afatinib-encapsulated micelles displayed higher cytotoxic activity in HCT - 15 cells and were more effective for tumor growth suppression in HCT - 15 - induced tumor xenografts than afatinib performance alone . Taken together , these findings suggest that higher serum P04626 REA levels reflect the higher P04626 REA contents in tumors of CRC patients , and the improved afatinib-encapsulated micelles possess high therapeutic efficacy in P04626 REA - overexpressed CRC in vitro and in vivo .

DB08916 SUB for Erlotinib Refractory Brain Metastases in a Patient with P00533 REA - Mutant Non-Small-Cell Lung Cancer : Can High-Affinity TKI Substitute for High-Dose TKI ?

Irreversible P00533 REA - TKIs : dreaming perfection . In the last few years , the treatment of Non-Small-Cell Lung Cancer ( NSCLC ) has dramatically changed . Presence of activating mutations in the Epidermal Growth Factor Receptor ( P00533 REA ) identified a particular group of NSCLC patients with different clinical characteristics and outcome . For P00533 REA mutant patients first-generation P00533 REA tyrosine-kinase inhibitors ( TKIs ) , such as gefitinib and erlotinib , represent the best therapeutic option in first , second and maintenance setting . Unfortunately , all patients develop acquired resistance and despite an initial benefit , virtually all patients progress due to the development of resistance . Several molecular mechanisms are responsible for acquired resistance and the two prominent are the up-regulation of the downstream signal by mesenchymal-epidermal transition ( MET ) amplification and the emergence of T790M P00533 REA gatekeeper mutation . Preclinical and early clinical trials suggested a potential efficacy of a new class of panHER inhibitor , also called irreversible or covalent inhibitor , in overcome acquired resistance related to T790M . DB08916 SUB , dacomitinib and neratinib , are currently in development in different setting and results from these trials are awaited in order to establish the role of these new compounds in the treatment of NSCLC .

Temporal molecular and biological assessment of an erlotinib-resistant lung adenocarcinoma model reveals markers of tumor progression and treatment response . Patients with lung cancer with activating mutations in the P01133 REA receptor ( P00533 REA ) kinase , who are treated long-term with tyrosine kinase inhibitors ( TKI ) , often develop secondary mutations in P00533 REA associated with resistance . Mice engineered to develop lung adenocarcinomas driven by the human P00533 REA T790M resistance mutation are similarly resistant to the P00533 REA TKI erlotinib . By tumor volume endpoint analysis , these mouse tumors respond to DB08916 SUB ( an irreversible P00533 REA / P04626 REA TKI ) and rapamycin combination therapy . To correlate P00533 REA - driven changes in the lung with response to drug treatment , we conducted an integrative analysis of global transcriptome and metabolite profiling compared with quantitative imaging and histopathology at several time points during tumor progression and treatment . Responses to single-drug treatments were temporary , whereas combination therapy elicited a sustained response . During tumor development , metabolomic signatures indicated a shift to high anabolic activity and suppression of antitumor programs with 11 metabolites consistently present in both lung tissue and blood . Combination drug treatment reversed many of the molecular changes found in tumored lung . Data integration linking cancer signaling networks with metabolic activity identified key pathways such as glutamine and glutathione metabolism that signified response to single or dual treatments . Results from combination drug treatment suggest that metabolic transcriptional control through C-MYC and SREBP , as well as ELK 1 , NRF 1 , and Q16236 , depends on both P00533 REA and mTORC 1 signaling . Our findings establish the importance of kinetic therapeutic studies in preclinical assessment and provide in vivo evidence that TKI-mediated antiproliferative effects also manifest in specific metabolic regulation .

Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . DB00191 MEN produces a spectrum of concentration-dependent biochemical effects . It interacts with NE transporters at 0.1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 REA at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 REA . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 REA does not metabolize platelet 5 - HT , and since amphetamine-type drugs are even weaker inhibitors of P27338 REA than P21397 REA . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 REA than phentermine , does not inhibit P21397 REA at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .

Epidermal growth factor enhances androgen receptor ‑ mediated bladder cancer progression and invasion via potentiation of AR transactivation . P10275 REA ( AR ) plays a critical role in bladder cancer ( BCa ) development . Our early studies found AR knock-out mice ( with few androgens and deleted AR ) failed to develop BCa , yet 50 % of castrated mice ( with few androgens and existing AR ) still developed BCa in an N-butyl-N - ( 4 - hydroxybutyl ) nitrosamine ( BBN ) carcinogen-induced BCa mouse model , suggesting the existing AR in BCa of castrated mice may still play important roles in promoting BCa development at the castration level of androgens . The mechanism underlying this and / or which factors potentiate AR function at the castration level of androgen remains unclear . Epidermal growth factor ( P01133 REA ) , a key player in BCa progression , has been demonstrated to be able to potentiate AR transactivation in prostate cancer . In the present study , we found that P01133 REA could increase BCa cell growth , migration and invasion in the presence of AR under the low amount of androgen and P01133 REA was able to potentiate AR transactivation through P00533 REA by activating PI3K / AKT and MAPK pathway at castration androgen level . The increased suppression effects by P00533 REA inhibitor of PD168393 on AR function after addition of anti-androgen , DB01128 , further suggested AR might play a key role in the effects of P01133 REA on BCa progression and metastasis . Collectively , our results indicate that P01133 REA may be able to potentiate AR transactivation that leads to enhancing BCa progression , which may help us to develop a better therapeutic approach to treat BCa via targeting both P01133 REA and AR signaling .

DB08916 SUB for the treatment of advanced non-small-cell lung cancer . INTRODUCTION : The inhibition of the epidermal growth factor receptor ( P00533 REA ) through tyrosine kinase inhibitors ( TKIs ) represents an effective strategy for P00533 REA - mutated NSCLC . DB08916 SUB is an irreversible erythroblastosis oncogene B ( ErbB ) family blocker , able to inhibit the kinase domains of P00533 REA , P04626 REA and Q15303 REA , and the transphosphorylation of ErbB 3 that has recently been approved in the United States for the first-line treatment of P00533 REA - mutated NSCLC and in Europe and Japan for the treatment of P00533 REA - mutated TKI-naive patients . AREAS COVERED : The authors analyzed the pharmacology and the clinical activity of afatinib in NSCLC through a review of the literature . Trials exploring different settings have been reported , including LUX-Lung 3 and LUX-Lung 6 , where the drug achieved better outcomes in terms of response rate , progression-free survival and quality of life compared with chemotherapy . The main toxicities of afatinib are gastrointestinal and skin-related adverse events . EXPERT OPINION : DB08916 SUB showed remarkable efficacy as a first-line treatment in the presence of common P00533 REA mutations . DB08916 SUB showed some activity in NSCLC with acquired resistance to P00533 REA TKIs , although , currently , its efficacy after the failure of erlotinib or gefitinib has not been clearly stated . Direct clinical data comparing the activity and tolerability of different inhibitors are still needed .

An update on molecularly targeted therapies in second - and third-line treatment in non-small cell lung cancer : focus on P00533 REA inhibitors and anti-angiogenic agents . DB01248 , pemetrexed and epidermal growth factor receptor tyrosine kinase inhibitors ( gefitinib and erlotinib ) are recommended second-line therapy for advanced non-small cell lung cancer ( NSCLC ) patients with disease progression . Although erlotinib is the only recommended third-line therapy , several drugs are being used in the clinic . Recent studies have focused on combining targeted agents with approved therapies , including broad-spectrum multikinase inhibitors targeting multiple ErbB Family receptors and multitargeted anti-angiogenic agents targeting the vascular endothelial growth factor receptor , platelet-derived growth factor receptor and fibroblast growth factor receptor pathways . Here , we review targeted therapies that are being evaluated in second - and third-line settings in NSCLC , including the ErbB Family Blocker afatinib ( DB08916 SUB ) , multityrosine kinase inhibitors ( pelitinib [ Q9Y259 REA - 56 ] ) , neratinib [ HKI - 272 ] , canertinib [ DB05424 ] , lapatinib [ GW - 572016 ] , dacomitinib [ PF - 299804 ] ) and multitargeted anti-angiogenic agents ( vandetanib [ DB05294 ] , sunitinib [ SU11248 ] , sorafenib [ BAY 43-9006 ] , nintedanib [ BIBF 1120 ] , axitinib [ AG - 013736 ] , cediranib [ DB04849 ] , motesanib [ Q99217 REA 706 ] , linifanib [ ABT 869 ] and pazopanib [ DB06589 ] ) .

DB08916 SUB prolongs survival compared with gefitinib in an epidermal growth factor receptor-driven lung cancer model . An irreversible ErbB family blocker is expected to inhibit tumors with activating epidermal growth factor receptor ( P00533 REA ) mutations more strongly than reversible P00533 REA tyrosine kinase inhibitors and to overcome acquired resistance to the T790M secondary mutation . Eleven-week-old transgenic mice with Egfr exon 19 deletion mutation were treated with afatinib , gefitinib , or vehicle for 4 weeks . All mice were sacrificed at 15 weeks of age , and the number of superficial left lung tumors with a long axis exceeding 1 mm was counted . The afatinib-treated group had significantly fewer tumors than the vehicle group ( P < 0.01 ) and tended to have fewer tumors than the gefitinib-treated group ( P = 0.06 ) . Pathologically , gefitinib-treated mice had clearer , more nodular tumors than afatinib-treated mice . Immunoblotting showed that afatinib suppressed not only pEGFR but also pHER 2 , and induced apoptosis for longer periods than gefitinib . Subsequently , when each drug was administered 5 days per week until death , afatinib significantly enhanced mouse survival compared with gefitinib ( median survival time : 456 days vs . 376.5 days ; log-rank test , P < 0.01 ) . Finally , the combination of afatinib with bevacizumab was found to be superior to either drug alone in exon 19 deletion / T790M and L858R / T790M xenograft tumors . Overall , afatinib was more potent than gefitinib in tumors harboring an exon 19 deletion mutation , and the combination of afatinib with bevacizumab efficiently suppressed tumors harboring the T790M secondary mutation .

Irreversible P00533 REA inhibitors in the treatment of advanced NSCLC . The epidermal growth factor receptor ( P00533 REA ) is among the most important targets in the treatment of advanced non-small cell lung cancer ( NSCLC ) . Erlotinib and gefitinib , two small molecules , are reversible P00533 REA tyrosine kinase inhibitors ( TKIs ) . Non-small cell lung cancers with P00533 REA mutations , are characterized by excellent responses when treated with the P00533 REA - TKIs gefitinib and erlotinib . However , all the patients with tumors harbouring P00533 REA mutations experience disease progression after a median of 10 to 14 months of treatment with gefitinib or erlotinib . A group of new generation P00533 REA - TKIs irreversibly inhibit P00533 REA - TK and represent one of the strategies that may potentially overcome the acquired resistance to gefitinib and erlotinib or achieve better outcomes than reversible inhibitors in the first-line treatment of P00533 REA mutant lung cancers . DB08916 SUB ( DB08916 SUB ) and PF299804 are the irreversible P00533 REA - TKIs with the most relevant data in the treatment of advanced NSCLC , as primary P00533 REA - targeted therapy and after resistance to reversible P00533 REA - TKIs . However , to date , the role of irreversible P00533 REA inhibitors remains to be defined .

The role of irreversible HER family inhibition in the treatment of patients with non-small cell lung cancer . Small-molecule tyrosine kinase inhibitors ( TKIs ) of the human epidermal growth factor receptor ( HER ) include the reversible epidermal growth factor receptor ( P00533 REA / HER - 1 ) inhibitors gefitinib and erlotinib . P00533 REA TKIs have demonstrated activity in the treatment of patients with non-small cell lung cancer ( NSCLC ) harboring activating P00533 REA mutations ; however , multiple mechanisms of resistance limit the benefit of these drugs . Although resistance to P00533 REA TKIs can be intrinsic and correlated with molecular lesions such as in Kirsten rat sarcoma viral oncogene homolog ( P01116 REA ; generally observed in a wild-type P00533 REA background ) , acquired resistance to P00533 REA TKIs can evolve in the setting of activating P00533 REA mutations , such as in the case of P00533 REA T790M mutations . Several irreversible inhibitors that target multiple members of the HER family simultaneously are currently in clinical development for NSCLC and may have a role in the treatment of TKI-sensitive and TKI-resistant disease . These include PF00299804 , an inhibitor of P00533 REA / HER - 1 , HER - 2 , and HER - 4 , and afatinib ( DB08916 SUB ) , an inhibitor of P00533 REA / HER - 1 , HER - 2 , and HER - 4 . Results of large , randomized trials of these agents may help to determine their potential for the treatment of NSCLC .

Nimotuzumab suppresses epithelial-mesenchymal transition and enhances apoptosis in low-dose UV-C treated salivary adenoid cystic carcinoma cell lines in vitro . Salivary adenoid cystic carcinoma ( SACC ) , which is one of the most common malignant tumors of the salivary glands , is associated with a poor long-term outcome . There are currently few therapeutic options for patients with SACC . Recent studies have shown the potential of the application of ultraviolet-C ( UV-C ) irradiation for the treatment of human cancer . In the present study , we investigated the effects of UV-C in the SACC cell lines SACC - 83 and SACC-LM . High-dose UV-C ( 200 J / m ) induced apoptosis and inhibited colony formation significantly . However , low-dose UV-C ( 10 J / m ) , which had little effect on apoptosis and colony formation , increased the ability of migration in SACC cells accompanied by a decrease in P12830 REA and an increase in vimentin , suggesting the occurrence of epithelial-mesenchymal transition ( EMT ) . Low-dose UV-C ( 10 J / m ) also resulted in upregulation of the phosphorylated forms of epidermal growth factor receptor ( P00533 REA ) and Akt ( p - P00533 REA and p-Akt , respectively ) . Pretreatment with Nimotuzumab , an anti - P00533 REA monoclonal antibody , reversed the EMT as well as upregulation of p - P00533 REA / p-Akt induced by UV-C . Moreover , Nimotuzumab enhanced UV-C induced apoptosis and inhibition of colony formation . Our results indicate that EMT exerts a protective effect against apoptosis induced by low-dose UV-C . Thus , the combined application of Nimotuzumab and low-dose UV-C in vitro has an advantageous antitumor effect in SACC compared with the application of UV-C alone .

A phase II study of afatinib ( DB08916 SUB ) , an irreversible ErbB family blocker , in patients with P04626 REA - positive metastatic breast cancer progressing after trastuzumab . DB08916 SUB is an oral , ErbB family blocker , which covalently binds and irreversibly blocks all kinase-competent ErbB family members . This phase II , open-label , single-arm study explored afatinib activity in human epidermal growth factor receptor 2 ( P04626 REA ) - positive breast cancer patients progressing after trastuzumab treatment . Patients had stage IIIB / IV P04626 REA - positive metastatic breast cancer , with progression following trastuzumab or trastuzumab intolerance and an Eastern Cooperative Oncology Group ( ECOG ) performance status of 0-2 . Patients received 50 mg afatinib once-daily until disease progression . Primary endpoint was objective response rate ( Response Evaluation Criteria in Solid Tumors 1.0 ) , with tumor assessments every 8 weeks . Forty-one patients were treated . Patients had received a median of three prior chemotherapy lines ( range , 0-15 ) and 68.3 % had received trastuzumab for > 1 year . Four patients ( 10 % of 41 treated ; 11 % of evaluable patients ) had partial response . Fifteen patients ( 37 % of 41 ) had stable disease as best response and 19 ( 46 % of 41 ) achieved clinical benefit . Median progression-free survival was 15.1 weeks ( 95 % confidence interval [ CI ] : 8.1- 16.7 ) ; median overall survival was 61.0 weeks ( 95 % CI : 56.7- not evaluable ) . Most frequent common terminology criteria for adverse events grade 3 treatment-related adverse events were diarrhea ( 24.4 % ) and rash ( 9.8 % ) . DB08916 SUB monotherapy was associated with promising clinical activity in extensively pretreated P04626 REA - positive breast cancer patients who had progressed following trastuzumab treatment .

Association of genetic polymorphisms with personality profile in individuals without psychiatric disorders . OBJECTIVE : Population-based twin studies demonstrate that approximately 40-50 % of the variability in personality dimensions results from genetic factors . This study assessed selected polymorphisms in the P21964 REA Val 158Met , P21397 REA 3 ' VNTR , 5HTTLPR , 102T / C 5 - Q13049 REA , Q01959 REA 3 ' VNTR and P14416 REA exon 8 genes and evaluated their association with personality profiles , anxiety levels , and depressiveness in healthy subjects . METHODS : This study included 406 unrelated ( mean age 38.51 years ) , mentally and somatically healthy Caucasian subjects of Polish origin . The prevalence of the gene variants mentioned above and their association with personality profiles , anxiety levels , and depressiveness was assessed using the Temperament and Character Inventory , NEO Five-Factor Inventory , Spielberger ' s State-Trait Anxiety Inventory and Beck ' s Depression Inventory . RESULTS : The effects of the 5HTTLPR gene on the s / s genotype and empathy ( P06681 REA ) were lowest in the entire group . The effects of gender , age and the Q13049 REA gene for the T / T genotype and attachment ( Q7Z3Z2 ) were highest in women . The effects of gender , age and the Q01959 REA gene on the 9/9 Q01959 REA genotype , compassion ( C4 ) and cooperativeness ( C ) were lowest in women . The effects of gender , age and the P21964 REA gene on the DB00134 / DB00134 genotype and neuroticism ( P04626 REA ) NEO-FFI were also lowest in women . CONCLUSIONS : Our results suggest considerable influence of individual genes on the formation of personality traits .

Clinical perspective of afatinib in non-small cell lung cancer . Reversible DB00171 - competitive inhibitors targeting the epidermal growth factor receptor ( P00533 REA ) have been established as the most effective treatment of patients with advanced non-small cell lung cancer ( NSCLC ) harboring " activating " mutations in exons 19 and 21 of the P00533 REA gene . However , clinical activity is limited by acquired resistance which on average develops within 10 months of continued treatment . The mechanisms for acquired resistance include selection of the P00533 REA T790M mutation in approximately 50 % of cases , and MET gene amplification , P42336 REA gene mutation , transdifferentiation into small-cell lung cancer and additional rare or unkown mechanisms . DB08916 SUB is a small molecule covalently binding and inhibiting the P00533 REA , P04626 REA and Q15303 REA receptor tyrosine kinases . In preclinical studies , afatinib not only inhibited the growth of models with common activating P00533 REA mutations , but was also active in lung cancer models harboring wild-type P00533 REA or the P00533 REA L858R / T790M double mutant . Clinical efficacy of afatinib has been extensively studied in the LUX-Lung study program . These trials showed promising efficacy in patients with P00533 REA - mutant NSCLC or enriched for clinical benefit from P00533 REA tyrosine kinase inhibitors gefitinib or erlotinib . Here we review the current status of clinical application of afatinib in NSCLC . We also discuss clinical aspects of resistance to afatinib and strategies for its circumvention .

DB08916 SUB for the treatment of metastatic non-small cell lung cancer . Targeting the epidermal growth factor receptor ( P00533 REA ) in patients with non-small cell lung cancer ( NSCLC ) harboring sensitizing mutations in the tyrosine kinase ( TKI ) domain has led to a significant change in the management of this disease . The classic or sensitizing mutations are G719X mutation in exon 18 , in-frame deletions or insertion of exon 19 , L858R or L861Q mutation in exon 21 . Approximately 90 % of these mutations are exon 19 deletion or exon 21 L858R point mutation . Gefitinib and erlotinib are reversible first-generation inhibitors of mutant P00533 REA , and treatment with these agents in the first-line setting has demonstrated a progression-free survival of 9.5- 13.7 months . However , the majority of these patients ultimately develop resistance to these drugs . DB08916 SUB is an irreversible pan-ErbB inhibitor that was developed to circumvent the problem of resistance to first-generation TKIs . The LUX-Lung studies have evaluated the efficacy and toxicities of afatinib in treatment-naïve and refractory NSCLC patients . The promising results of some of these trials led to approval of afatinib by the US Food and Drug Administration for patients with advanced NSCLC and P00533 REA exon 19 deletions or exon 21 ( L858R ) substitution mutations . DB08916 SUB causes toxicities similar to those of the first-generation P00533 REA TKIs , such as diarrhea , rash , acne , and stomatitis , and overall is well tolerated . This article focuses on the clinical studies of afatinib in patients with NSCLC .

Determination of fenofibric acid concentrations by HPLC after anion exchange solid-phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride-lowering response to the lipid-lowering drug fenofibrate require quantification of the active acidic form of this Q07869 REA agonist . Anion-exchange solid-phase extraction , in combination with reverse-phase high-performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady-state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over-the-counter nonsteroidal anti-inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . DB01039 MEN analysis was found to be linear over the range of 0.5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98.65 % to 102.4 % , whereas the within - and between-day precisions ranged from 1.0 % to 2.2 % and 2.0 % to 6.2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion-exchange solid-phase extraction in combination with reverse-phase HPLC accurately determines steady-state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .

A transgenic platform for testing drugs intended for reversal of cardiac remodeling identifies a novel 11βHSD1 inhibitor rescuing hypertrophy independently of re-vascularization . RATIONALE : Rescuing adverse myocardial remodeling is an unmet clinical goal and , correspondingly , pharmacological means for its intended reversal are urgently needed . OBJECTIVES : To harness a newly-developed experimental model recapitulating progressive heart failure development for the discovery of new drugs capable of reversing adverse remodeling . METHODS AND RESULTS : A P15692 REA - based conditional transgenic system was employed in which an induced perfusion deficit and a resultant compromised cardiac function lead to progressive remodeling and eventually heart failure . Ability of candidate drugs administered at sequential remodeling stages to reverse hypertrophy , enlarged LV size and improve cardiac function was monitored . Arguing for clinical relevance of the experimental system , clinically-used drugs operating on the P00797 REA - Angiotensin - DB04630 - System ( RAAS ) , namely , the P12821 REA inhibitor Enalapril and the direct renin inhibitor Aliskerin fully reversed remodeling . Remodeling reversal by these drugs was not accompanied by neovascularization and reached a point-of-no-return . Similarly , the PPARγ agonist Pioglitazone was proven capable of reversing all aspects of cardiac remodeling without affecting the vasculature . Extending the arsenal of remodeling-reversing drugs to pathways other than RAAS , a specific inhibitor of 11β - hydroxy-steroid dehydrogenase type 1 ( 11β HSD 1 ) , a key enzyme required for generating active glucocorticoids , fully rescued myocardial hypertrophy . This was associated with mitigating the hypertrophy-associated gene signature , including reversing the myosin heavy chain isoform switch but in a pattern distinguishable from that associated with neovascularization-induced reversal . CONCLUSIONS : A system was developed suitable for identifying novel remodeling-reversing drugs operating in different pathways and for gaining insights into their mechanisms of action , exemplified here by uncoupling their vascular affects .

Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen-only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to DB00294 MEN users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo-pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post-treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre-decidualized state by 48 h post-treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 REA - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor-positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using DB00294 MEN who were treated with a single dose of mifepristone .

Targeting androgen receptor in estrogen receptor-negative breast cancer . Endocrine therapies for breast cancer that target the estrogen receptor ( ER ) are ineffective in the 25 % - 30 % of cases that are ER negative ( ER - ) . P10275 REA ( AR ) is expressed in 60 % - 70 % of breast tumors , independent of ER status . How androgens and AR regulate breast cancer growth remains largely unknown . We find that AR is enriched in ER - breast tumors that overexpress P04626 REA . Through analysis of the AR cistrome and androgen-regulated gene expression in ER - / P04626 REA + breast cancers we find that AR mediates ligand-dependent activation of Wnt and P04626 REA signaling pathways through direct transcriptional induction of P56706 REA and P21860 REA . Specific targeting of AR , Wnt or P04626 REA signaling impairs androgen-stimulated tumor cell growth suggesting potential therapeutic approaches for ER - / P04626 REA + breast cancers .

Q07869 REA ligands decrease human airway smooth muscle cell migration and extracellular matrix synthesis . Airway smooth muscle cells produce extracellular matrix proteins , which in turn can promote smooth muscle survival , proliferation and migration . Currently available therapies have little effect on airway smooth muscle matrix production and migration . Peroxisome proliferator-activated receptor ( Q07869 REA ) ligands are reported to decrease migration and matrix production in various cell lines . In this study , we examined the effect of Q07869 REA ligands on human airway smooth muscle ( HASM ) matrix production and migration . Q07869 REA expression was examined by RT-PCR and Western blotting . Endogenous Q07869 REA activity was examined by transfecting cells with a Q07869 REA response element-luciferase reporter plasmid . We observed that HASM cells express PPARα , β and γ . A six-fold induction of luciferase activity was observed by stimulating cells with a pan-agonist , indicating endogenous Q07869 REA activity . The Q07869 REA ligands ciglitazone , 15 - deoxy-Δ 12,14- prostaglandin J ( 2 ) and WY - 14643 decreased migration towards platelet-derived growth factor receptor . This was not mediated by inhibiting Akt phosphorylation or promoting P60484 REA activity , but partly through cyclooxygenase - 2 induction and prostaglandin E ( 2 ) production that increased cyclic AMP levels in the cells . All three ligands also caused an inhibition of collagen and fibronectin secretion by cultured smooth muscle cells . We conclude that Q07869 REA ligands decrease HASM migration and matrix production and are , therefore , potentially useful for modulating airway remodelling .

The effect of acquired cisplatin resistance on sensitivity to P00533 REA tyrosine kinase inhibitors in P00533 REA mutant lung cancer cells . Although epidermal growth factor receptor tyrosine kinase inhibitors ( P00533 REA TKIs ) are used as first-line agents for treating nonsquamous cell lung cancer with P00533 REA mutation , there are many patients who have to receive these drugs following platinum-based chemotherapy . This study was designed to define whether exposure to cisplatin could affect the sensitivity to P00533 REA TKIs because conflicting results have been presented . We established sublines that are resistant to cisplatin from P00533 REA wild-type cells ( A549 and H460 ) and P00533 REA mutant cells ( PC - 9 and HCC 827 ) . The P00533 REA - related signals were examined by Western blotting . MTT assay and the trypan blue exclusion method were used for the in vitro study , while tumor size and the SUV of the 18FDG - PET scans were measured in animal models . The IC50 value and apoptotic fractions after exposure to P00533 REA TKIs , such as gefitinib , erlotinib , and DB08916 SUB , were almost the same in the cisplatin-resistant sublines compared to that of the parent cells . Although the baseline P60484 REA expression was reduced in the resistant cells , as was indicated in a previous study , the P00533 REA - related signals similarly responded to the P00533 REA TKIs . Furthermore , the reduced tumor size and SUV of the 18FDG - PET of the implanted tumor in nude mice according to erlotinib treatment were not different between the resistant sublines and the parent cells . In conclusion , the acquired resistance to cisplatin did not affect the sensitivity to P00533 REA TKIs in the P00533 REA mutant lung cancer cells , and this should abrogate any concerns about the use of P00533 REA TKIs following platinum-based chemotherapy .

Effects of Q07869 REA agonists on proliferation and differentiation in human urothelium . Systemic treatment of rats with peroxisome proliferator-activated receptor ( Q07869 REA ) agonists ( mainly of dual alpha / gamma activity ) has indicated that they may invoke non-genotoxic carcinogenesis in the epithelial lining of the urinary tract ( urothelium ) . Although there is evidence in the male rat to support an indirect effect via a crystaluria-induced urothelial damage response , there is other evidence to indicate a direct signalling effect on the urothelium and hence the full implication for using these drugs in man is unclear . Numerous reports have demonstrated that PPARs are expressed within the urothelium of different species , including man , and from an early developmental stage . We have developed methods to maintain normal human urothelial ( NHU ) cells in culture , where the cells retain Q07869 REA expression and express a highly proliferative phenotype , mediated via autocrine stimulation of the epidermal growth factor ( P01133 REA ) receptor . We have shown that specific activation of PPARgamma results in a programme of gene expression changes associated with late / terminal cytodifferentiation , including induction of cytokeratins CK13 and CK20 , tight junction-associated claudin 3 , and uroplakins UPK 1a and O00526 , but this is dependent upon inhibition of the signalling cascade downstream of the P01133 REA receptor . This indicates a subtle balance in the regulation of proliferation and differentiation in urothelium , with PPARgamma agonists promoting differentiation . Our data indicate that human urothelium is a target tissue for PPARgamma signalling , but it has yet to be determined whether dual agonists could have a modulatory effect on the proliferation / differentiation balance .

Identification of candidate small-molecule therapeutics to cancer by gene-signature perturbation in connectivity mapping . Connectivity mapping is a recently developed technique for discovering the underlying connections between different biological states based on gene-expression similarities . The sscMap method has been shown to provide enhanced sensitivity in mapping meaningful connections leading to testable biological hypotheses and in identifying drug candidates with particular pharmacological and / or toxicological properties . Challenges remain , however , as to how to prioritise the large number of discovered connections in an unbiased manner such that the success rate of any following-up investigation can be maximised . We introduce a new concept , gene-signature perturbation , which aims to test whether an identified connection is stable enough against systematic minor changes ( perturbation ) to the gene-signature . We applied the perturbation method to three independent datasets obtained from the GEO database : acute myeloid leukemia ( AML ) , cervical cancer , and breast cancer treated with letrozole . We demonstrate that the perturbation approach helps to identify meaningful biological connections which suggest the most relevant candidate drugs . In the case of AML , we found that the prevalent compounds were retinoic acids and Q07869 REA activators . For cervical cancer , our results suggested that potential drugs are likely to involve the P00533 REA pathway ; and with the breast cancer dataset , we identified candidates that are involved in prostaglandin inhibition . Thus the gene-signature perturbation approach added real values to the whole connectivity mapping process , allowing for increased specificity in the identification of possible therapeutic candidates .

Novel drugs against non-small-cell lung cancer . PURPOSE OF REVIEW : Important therapeutic advances for patients with advanced non-small-cell lung cancer ( NSCLC ) with focus on individualized therapy have recently occurred and are summarized in this review . RECENT FINDINGS : Cetuximab added to first-line chemotherapy has been shown to improve survival in patients with high epidermal growth factor receptor ( P00533 REA ) expression in their tumors . DB08916 SUB has shown improved progression-free survival and better quality of life compared to chemotherapy in patients with P00533 REA - mutation-positive adenocarcinomas . Several other P00533 REA - directed agents are in clinical development . DB08865 improved progression-free survival compared to second-line chemotherapy with docetaxel or pemetrexed in patients with advanced anaplastic lymphoma kinase-positive NSCLC . Selumetinib added to docetaxel has improved outcome compared with docetaxel in a randomized phase II trial in patients with advanced P01116 REA - mutant NSCLC and this combination is currently studied in a phase III trial . DB09079 added to docetaxel improved progression-free survival in the second-line therapy of patients with advanced NSCLC but many other angiogenesis inhibitors failed to improve clinical outcome in phase III trials . Several other targeted therapies are currently evaluated in phase III trials in patients with advanced NSCLC . SUMMARY : Recent trials have led to the approval of afatinib and crizotinib for subsets of patients with advanced NSCLC .

Second-generation irreversible epidermal growth factor receptor ( P00533 REA ) tyrosine kinase inhibitors ( TKIs ) : a better mousetrap ? A review of the clinical evidence . The discovery of activating epidermal growth factor receptor ( P00533 REA ) mutations in non-small cell lung cancer ( NSCLC ) in 2004 heralded the era of molecular targeted therapy in NSCLC . First-generation small molecule , reversible tyrosine kinase inhibitors ( TKIs ) of P00533 REA , gefitinib and erlotinib , had been approved for second - or third-line treatment of NSCLC prior to the knowledge of these mutations . However , resistance to gefitinib and erlotinib invariably develops after prolonged clinical use . Two second-generation irreversible P00533 REA TKIs , afatinib ( DB08916 SUB ) and dacomitinib ( PF - 00299804 ) , that can potentially overcome the majority of these resistances are in late stage clinical development . Here I will review the clinical data of P00533 REA TKIs and discuss the appropriate future role of afatinib and dacomitinib in NSCLC : whether as replacement of erlotinib or gefitinib or only after erlotinib or gefitinib failure and whether different subgroups would benefit from different approaches .

P10275 REA - induced tumor suppressor , B2CW77 , inhibits breast cancer growth and transcriptionally activates p53 / p73 - mediated apoptosis in breast carcinomas . P10275 REA ( AR ) expression by immunohistochemistry correlates with better prognosis and survival among breast cancer patients . We and others have shown that AR inhibits proliferation and induces apoptosis in breast cancer cells . However , the mechanism of AR ' s anti-tumor effect in breast cancer is still not fully understood . Our recent study indicates that AR upregulates expression of tumor suppressor gene P60484 REA by promoter activation in breast cancer . B2CW77 , encoding B2CW77 protein , is a newly identified gene , which shares a bidirectional promoter with P60484 REA and is transcribed in the opposite direction . So far , the function of B2CW77 has never been studied in tumorigenesis . Here , we define B2CW77 as a tumor suppressor in breast carcinomas , which inhibits tumor growth and invasiveness . After analyzing 188 normal breast and 1247 malignant breast cancer tissues , we observed the loss of B2CW77 in multiple breast cancer subtypes and this decreased B2CW77 expression associates with tumor progression and increasing histological grade in invasive carcinomas . We characterize B2CW77 , for the first time , as a transcription factor , directly promoting the expression of P04637 REA and O15350 REA , with consequent elevated apoptosis and cell cycle arrest in breast cancer cells . We demonstrate , in vitro and in murine xenograph models , that both B2CW77 and P60484 REA are AR-target genes , mediating androgen-induced growth inhibition and apoptosis in breast cancer cells . Our observations suggest that B2CW77 might be used as a potential prognostic marker and novel therapy target for breast carcinomas .

DB08916 SUB and lung cancer . P00533 REA tyrosine kinase inhibitors ( P00533 REA - TKI ) have an established role in the treatment of non-small-cell lung cancer ( NSCLC ) . First-generation reversible DB00171 - competitive P00533 REA - TKIs are approved for the initial treatment of patients with P00533 REA mutation-positive advanced NSCLC . DB08916 SUB is an irreversible second-generation P00533 REA - TKI with potent preclinical activity against P00533 REA ( wild type and mutant ) , P04626 REA , Q15303 REA and P00533 REA - mutant NSCLC with acquired resistance to reversible P00533 REA - TKI . LUX-Lung 3 trial demonstrated superiority of afatinib to cisplatin and pemetrexed in the frontline treatment of treatment-naïve patients with advanced adenocarcinoma of the lung and P00533 REA mutation . Based on these results , afatinib was recently approved for the first-line treatment of NSCLC patients with P00533 REA mutation . This article summarizes current status of preclinical and clinical development of afatinib in NSCLC .

DB08916 SUB combined with cetuximab for lung adenocarcinoma with leptomeningeal carcinomatosis . We report a patient with non-small cell lung cancer ( NSCLC ) developed leptomeningeal carcinomatosis ( O15467 REA ) after 4 years of multiple treatments . High-dose tyrosine kinase inhibitor ( TKI ) was given for O15467 REA at first but was not effective . She then received dual therapy combining of afatinib and cetuximab . Brain magnetic resonance imaging ( Q9BWK5 ) showed a partial response of disease and the patient experienced a clinical benefit . Our case suggests that dual targeting of epidermal growth factor receptor ( P00533 REA ) by a combination of afatinib and cetuximab can be a potential novel treatment option in treating O15467 REA when high-dose TKI failed .

Management of the adverse events of afatinib : a consensus of the recommendations of the Spanish expert panel . DB08916 SUB is an irreversible ErbB family blocker tyrosine kinase inhibitor ( TKI ) , which has recently been approved for the treatment of patients with P00533 REA M + non-small cell lung cancer . As observed with reversible P00533 REA TKIs , it can induce class-effect adverse events . Appropriate management of afatinib-related adverse events improves quality of life and clinical outcomes in these patients . Here we provide practical recommendations for the prophylaxis and treatment of the most common of these ( e . g . , diarrhea , rash , mucositis and others ) .

P10275 REA rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration-resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen-androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR-targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with DB08899 MEN , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .

DB08916 SUB circumvents multidrug resistance via dually inhibiting DB00171 binding cassette subfamily G member 2 in vitro and in vivo . Multidrug resistance ( MDR ) to chemotherapeutic drugs is a formidable barrier to the success of cancer chemotherapy . Expressions of DB00171 - binding cassette ( DB01048 ) transporters contribute to clinical MDR phenotype . In this study , we found that afatinib , a small molecule tyrosine kinase inhibitor ( TKI ) targeting P00533 REA , HER - 2 and HER - 4 , reversed the chemoresistance mediated by Q9UNQ0 in vitro , but had no effect on that mediated by multidrug resistance protein P08183 REA and P33527 REA . In addition , afatinib , in combination with topotecan , significantly inhibited the growth of Q9UNQ0 - overexpressing cell xenograft tumors in vivo . Mechanistic investigations exhibited that afatinib significantly inhibited ATPase activity of Q9UNQ0 and downregulated expression level of Q9UNQ0 , which resulted in the suppression of efflux activity of Q9UNQ0 in parallel to the increase of intracellular accumulation of Q9UNQ0 substrate anticancer agents . Taken together , our findings may provide a new and useful combinational therapeutic strategy of afatinib with chemotherapeutical drug for the patients with Q9UNQ0 overexpressing cancer cells .

Phase I trial of oral P42345 REA inhibitor everolimus in combination with trastuzumab and vinorelbine in pre-treated patients with P04626 REA - overexpressing metastatic breast cancer . To determine the feasible dose and schedule for everolimus , an oral P42345 REA inhibitor , combined with vinorelbine and trastuzumab for patients with P04626 REA - overexpressing metastatic breast cancer pretreated with trastuzumab . In this phase Ib multicenter , Bayesian dose-escalation study , 50 patients received everolimus 5 mg / day , 20 mg / week , or 30 mg / week plus vinorelbine ( 25 mg / m² on day 1 and 8 every 3 weeks ) and trastuzumab ( 2 mg / kg weekly ) . Endpoints included end-of-cycle - 1 dose-limiting toxicity ( DLT ) rate ( primary endpoint ) , safety , relative dose intensity , overall response rate ( ORR ) , and pharmacokinetics . Grade 3/4 neutropenia was the most common end-of-cycle - 1 DLT and occurred in 10 of 30 and 4 of 14 patients in the 5 mg / day and 30 mg / week cohorts , respectively . Other end-of-cycle - 1 DLTs included single cases of febrile neutropenia , grade 3 stomatitis with concomitant fatigue , grade 2 stomatitis , grade 3 anorexia , and grade 2 acneiform dermatitis , all in the 5 - mg / day cohort . Based on the recorded DLTs and global safety , everolimus 5 mg / day and 30 mg / week were chosen as the optimal dose levels for the daily and weekly arms . Forty-seven patients were evaluable for efficacy . ORR was 19.1 % , with a disease control rate of 83.0 % and median progression-free survival of 30.7 weeks . No drug interaction was observed between everolimus and vinorelbine . DB01590 MEN combined with weekly vinorelbine and trastuzumab generally was well tolerated and had encouraging antitumor activity in heavily pretreated patients with P04626 REA - overexpressing metastatic breast cancer that progressed on trastuzumab ( NCT 00426530 ) .

[ DB08916 SUB ( DB08916 SUB ) ] . DB08916 SUB ( DB08916 SUB ) is an irreversible multi-target HER receptor tyrosine kinase inhibitor developed in patients with advanced solid tumours . Several phase I studies were conducted in patients with non-small cell lung cancer ( NSCLC ) , as a single agent or in combination . In further phase II or III studies , patients were selected based on the duration of response to first generation P00533 REA - TKI in previous line ( supposed to have greater chance to have an activating P00533 REA mutation ) or based directly on the P00533 REA activating mutation status . Here , we report and comment the main results of these studies in lung cancer patients . This drug has been approved by the Food and Drug Administration in June 2013 for the first-line treatment of patients with metastatic NSCLC whose tumours have P00533 REA mutation . In Europe , it has been approved in September 2013 in the same indication .

P00797 REA inhibition with aliskiren . 1 . Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X-ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . DB09026 MEN has a low bioavailability ( between 2.6 and 5.0 % ) compensated by its high potency to inhibit renin ( IC50 : 0.6 nmol / L ) and a long plasma half-life ( 23-36 h ) , which makes it suitable for once-daily dosing . 3 . The once-daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I-converting enzyme ( P12821 REA ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin-nitric oxide-cyclic guanosine monophosphate pathway and possibly the ( pro ) renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 REA inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study .

DB08916 SUB for the treatment of patients with P00533 REA - positive non-small cell lung cancer . P00533 REA ( P00533 REA ) tyrosine kinase inhibitors ( TKIs ) are valuable treatments for P00533 REA - mutated non-small cell lung cancer ( NSCLC ) . Anti - P00533 REA antibodies are widely used in the treatment of head and neck squamous cell carcinomas ( HNSCC ) and in P01116 REA wild-type colorectal cancer . The first-generation , reversible P00533 REA inhibitors erlotinib and gefitinib in the first-line setting provide superior progression-free survival and quality of life compared to conventional chemotherapy in NSCLC harboring activating P00533 REA mutations . However , these therapies eventually fail and new options are needed . DB08916 SUB is a novel irreversible inhibitor of the ErbB family members P00533 REA , tyrosine kinase-type cell surface receptors P04626 REA and Q15303 REA . It shows preclinical efficacy in NSCLC with common P00533 REA - activating mutations and the T790M mutation typically associated with P00533 REA TKI resistance . Preclinical activity is seen in other tumor types as well , including HNSCC . Clinically , afatinib has been evaluated in the broad-reaching LUX Lung trial program , with significant activity seen in the first and later-line settings . It is also under investigation in multiple other tumor types . This review will stress on afatinib ' s preclinical pharmacology , pharmacokinetics and clinical activity with a focus on NSCLC .

Second and third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer . PURPOSE OF REVIEW : The first-generation epidermal growth factor receptor tyrosine kinase inhibitors ( P00533 REA - TKIs ) , gefitinib and erlotinib , are effective as first-line treatment of advanced nonsmall cell lung cancer ( NSCLC ) harboring activating P00533 REA mutations ( deletions in exon 19 and exon 21 L858R mutation ) . P00533 REA T790 M resistance mutation ( P00533 REA T790 M ) ultimately emerged in most of these patients . The second and third-generation P00533 REA - TKIs were designed to have more potent inhibition of P00533 REA and to overcome P00533 REA T790 M . This review describes the recent developments of these novel P00533 REA - TKIs . RECENT FINDINGS : The second-generation P00533 REA - TKIs , afatinib and dacomitinib , irreversibly bind to the tyrosine kinase of P00533 REA and other ErbB-family members . DB08916 SUB has been approved as first-line treatment of advanced NSCLC harboring activating P00533 REA mutations . Dacomitinib is under development . Third-generation P00533 REA - TKIs , AZD 9291 , CO - 1686 , and HM61713 , inhibit both P00533 REA activating and resistance mutations , while sparing wild-type P00533 REA . In early-phase studies , these drugs demonstrated promising response rates against tumors with acquired P00533 REA T790 M . SUMMARY : Second-generation P00533 REA - TKI , afatinib , is available as first-line treatment of advanced NSCLC harboring activating P00533 REA mutations . Third-generation P00533 REA - TKIs are under development for tumors harboring acquired P00533 REA T790 M .

Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender-dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti-estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element-driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 REA ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 REA protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 REA expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 REA and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .

Clinical and comparative utility of afatinib in non-small cell lung cancer . The first targeted agents approved for non-small cell lung cancer ( NSCLC ) treatment , the epidermal growth factor receptor ( P00533 REA ) tyrosine kinase inhibitors ( TKIs ) gefitinib and erlotinib , have an impressive activity in the presence of activating mutations of the P00533 REA gene . However , all patients develop acquired resistance principally through secondary mutations ( T790M ) , P04626 REA amplification , MET amplification , and other molecular aberrations . An attempt to overcome P00533 REA TKI resistance has been through the development of irreversible blockers . DB08916 SUB is an irreversible inhibitor of the tyrosine kinase activity of all members of the HER family . The pharmacologic properties of afatinib ( formation of covalent bonds , inhibition of other family members , and in vitro and in vivo activity on T790M mutation positive tumors ) made this drug particularly appealing to study in clinic . Therefore , an intense program of clinical research ( LUX-Lung program ) was started and clinical results have shown very encouraging activity profiles in patients harboring P00533 REA activating mutations and in those with acquired resistance to reversible TKIs .

DB08916 SUB : emerging next-generation tyrosine kinase inhibitor for NSCLC . The discovery of epidermal growth-factor receptor ( P00533 REA ) - activating mutations and the introduction of oral P00533 REA tyrosine kinase inhibitors ( P00533 REA - TKIs ) have expanded the treatment options for patients with non-small cell lung cancer . The first two reversible P00533 REA - TKIs , erlotinib and gefitinib , are approved for use in the first-line setting in patients with known P00533 REA - activating mutations and in the second - and third-line settings for all NSCLC patients . These first-generation P00533 REA - TKIs improve progression-free survival when compared to chemotherapy in patients with P00533 REA - activating mutations in the first-line setting . However , nearly all patients develop resistance to P00533 REA - directed agents . There is a need for further therapy options for patients with disease progression after treatment with reversible P00533 REA - TKIs . DB08916 SUB is an irreversible ErbB family blocker that inhibits P00533 REA , P04626 REA , and Q15303 REA . In vitro and in vivo , afatinib have shown increased inhibition of the common P00533 REA - activating mutations as well as the T790M resistance mutation when compared to erlotinib and gefitinib . Clinically , afatinib has been evaluated in the LUX-Lung series of trials , with improvement in progression-free survival reported in patients with P00533 REA - activating mutations in both first - and second - / third-line settings when compared to chemotherapy . Further investigation is needed to determine the precise role that afatinib will play in the treatment of patients with non-small cell lung cancer and P00533 REA - activating mutations .

Phase II , open-label trial to assess QTcF effects , pharmacokinetics and antitumor activity of afatinib in patients with relapsed or refractory solid tumors . PURPOSE : DB08916 SUB is an irreversible ErbB family blocker currently under evaluation in late-stage clinical trials . This study primarily assessed the cardiac safety , pharmacokinetics and antitumor activity of afatinib in cancer patients . METHODS : In this multicenter , Phase II , open-label , single-arm trial , 60 patients with solid tumors who were expected to express epidermal growth factor receptor - 1 and P04626 REA received oral afatinib 50 mg daily . QTcF intervals ( QT interval corrected by the Fridericia formula ) were evaluated based on electrocardiogram recordings time-matched with pharmacokinetic blood samples after single ( Day 1 ) and continuous ( Day 14 ; steady state ) administration . Adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events ( NCI CTCAE ) , version 3.0 ; antitumor activity was assessed using RECIST 1.0 . RESULTS : There was a nonsignificant decrease of 0.3 ms ( 90 % confidence interval -2.8 , 2.3 ; N = 49 ) in the mean of the average time-matched QTcF interval from baseline to steady state . The maximum plasma concentration for afatinib was seen at median tmax 3 h after both single dose and at steady state . No relationship between afatinib plasma concentrations and time-matched QTcF , QT and heart rate change was found . The overall adverse event profile was consistent with the known safety profile of afatinib . One patient demonstrated a partial response ( PR ) and two patients unconfirmed PRs . CONCLUSIONS : DB08916 SUB had no impact on cardiac repolarization , had a manageable safety profile and demonstrated antitumor activity in this uncontrolled study .

Strategies for overcoming resistance to P00533 REA family tyrosine kinase inhibitors . The first-generation epidermal growth factor receptor tyrosine kinase inhibitors erlotinib and gefitinib have been incorporated into treatment paradigms for patients with advanced non-small cell lung cancer . These agents are particularly effective in a subset of patients whose tumors harbor activating epidermal growth factor receptor mutations . However , most patients do not respond to these tyrosine kinase inhibitors , and those who do will eventually acquire resistance that typically results from a secondary epidermal growth factor receptor mutation ( e . g . , T790M ) , mesenchymal-epithelial transition factor amplification , or activation of other signaling pathways . For patients whose tumors have wild-type epidermal growth factor receptor , there are several known mechanisms of initial resistance ( e . g . , Kirsten rat sarcoma viral oncogene homolog mutations ) but these do not account for all cases , suggesting that unknown mechanisms also contribute . To potentially overcome the issue of resistance , next-generation tyrosine kinase inhibitors are being developed , which irreversibly block multiple epidermal growth factor receptor family members ( e . g . , afatinib [ DB08916 SUB ] and PF - 00299804 ) and / or vascular endothelial growth factor receptor pathways ( e . g . , BMS - 690514 and DB05007 ) . In addition , drugs that block parallel signaling pathways or signaling molecules downstream of the epidermal growth factor receptor , such as the insulin-like growth factor - 1 receptor and the mammalian target of rapamycin , are undergoing clinical evaluation . As drug resistance appears to be pleomorphic , combinations of drugs or drugs with multiple targets may be more effective in circumventing resistance .

DB08916 SUB ( DB08916 SUB ) development in non-small-cell lung cancer . DB08916 SUB ( DB08916 SUB ) , a novel aniline-quinazoline derivative , irreversibly and equipotently targets the intrinsic kinase activity of all active ErbB receptor family members . Preclinical results show that afatinib is effective in lung cancer models , including those with P01133 REA receptor ( P00533 REA ) mutations resistant to reversible first-generation P00533 REA inhibitors . DB08916 SUB is being investigated in the LUX-Lung program , which will evaluate afatinib as a first-line treatment in patients with P00533 REA - activating mutations ( LUX-Lung 2 , 3 and 6 ) and as a second - or third-line treatment in patients that have acquired resistance to gefitinib and / or erlotinib ( LUX-Lung 1 , 4 and 5 ) . LUX-Lung 1 and 2 have demonstrated , within their respective target groups , a significant increase in the disease control rate of 58 and 86 % , respectively , and significant prolongation of progression-free survival . Further Phase III clinical trials are currently ongoing to assess afatinib in combination with paclitaxel ( LUX-Lung 5 ) , and compared with cisplatin / pemetrexed ( LUX-Lung 3 ) or cisplatin / gemcitabine ( LUX-Lung 6 ) .

New strategies to overcome limitations of reversible P00533 REA tyrosine kinase inhibitor therapy in non-small cell lung cancer . The epidermal growth factor receptor ( P00533 REA ) , a member of the HER family of receptors , has become a well-established target for the treatment of patients with non-small cell lung cancer ( NSCLC ) . Several P00533 REA - targeted agents produce objective responses in a minority of unselected patients , but a majority of those with P00533 REA - activating mutations ; however , all responders eventually develop resistance . The modest activity of agents that target only P00533 REA may be due , in part , to the complexity and interdependency of HER family signaling . The interdependent signaling that occurs between P00533 REA and P04626 REA provides a rationale for the simultaneous inhibition of these receptors with reversible and irreversible inhibitors . Several agents with activity against both P00533 REA and P04626 REA are currently under development . Irreversible P00533 REA / P04626 REA tyrosine kinase inhibitors ( TKIs ) ( e . g . , DB08916 SUB , HKI - 272 ) and pan-HER TKIs ( e . g . , PF00299804 ) comprise a novel class of agents in clinical development that may prevent and overcome inherent and acquired resistance to first-generation reversible P00533 REA TKIs . Other agents in development include the monoclonal antibody pertuzumab , and XL - 647 , which inhibits P00533 REA and P04626 REA , as well as multiple vascular endothelial growth factor receptor family members . Here we briefly review the currently available P00533 REA - targeted agents , discuss the rationale for extending inhibition to other HER family members , weigh the merits of irreversible HER family inhibition , and summarize preclinical and clinical data with P00533 REA / P04626 REA and pan-HER inhibitors under clinical development .

Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 REA , P21397 REA , P23560 REA , NOS 3 , P05231 REA , P12036 , P31645 REA , P21964 REA , P48454 REA and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .

Generation of Epstein-Barr virus-specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein-Barr virus-specific cytotoxic T lymphocytes ( EBV-CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV-associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long-term persistence of transferred EBV-CTLs , precluding their use as prophylaxis . DB00864 MENMAX DB00864 MEN ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 REA ) . We have knocked down the expression of P62942 REA in EBV-CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 REA - silenced EBV-CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti-PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV-specific immune surveillance in patients at high risk of PTLD after transplantation .

[ A new perspective in the treatment of non-small-cell lung cancer ( NSCLC ) . Role of afatinib : An oral and irreversible ErbB family blocker ] . Tyrosine kinase inhibitors ( TKI ) that block epidermal growth factor receptor ( P00533 REA ) pathway have demonstrated a clinical benefit for patients with non-small-cell lung cancer ( NSCLC ) harboring P00533 REA mutations . The currently available TKI ( gefitinib and erlotinib ) are P00533 REA reversible inhibitors . DB08916 SUB is an oral , irreversible ErbB family blocker that covalently binds and blocks signaling from P00533 REA ( ErbB 1 ) , P04626 REA ( ErbB 2 ) and ErbB 4 . The compound inhibits also the transphosphorylation of ErbB 3 . With this mode of action , afatinib is thought to have a mechanistic advantage over P00533 REA blockade alone , in that it provides a sustained , covalent inhibition of ErbB homo - and hetero-dimers . In the pivotal LUX-Lung 3 study , afatinib demonstrated a prolonged progression free survival over standard pemetrexed plus cisplatin chemotherapy ( 11.1 versus 6.9 months ; HR = 0.58 , 95 % CI : 0.43- 0.78 ; P = 0.001 ) in P00533 REA mutation positive NSCLC patients . The compound has recently been granted a marketing authorization ( MA ) for the treatment of patients with locally advanced or metastatic NSCLC with activating P00533 REA mutation ( s ) and P00533 REA TKI-naive . In this paper are summarized the efficacy and safety data in this indication .

Invasive Lobular Carcinomas Do Not Express Basal Cytokeratin Markers CK5 / 6 , CK14 and CK17 . The expression of basal cytokeratin markers CK5 / 6 in breast carcinomas has been associated with high histological grade and poor clinical outcome . A previous study has shown that CK5 / 6 can be detected in up to 17 % of invasive lobular carcinomas ( Q9Y4X3 REA ) . Here we study the expression of three basal cytokeratin markers ( CK5 / 6 , CK14 , and CK17 ) in 53 Q9Y4X3 REA cases diagnosed by histology and lack of P12830 REA expression . Among them , 42 were classic lobular carcinomas , 6 were tubular-lobular carcinoma , and 5 were pleomorphic lobular carcinomas . There was no significant difference among these three groups in patients ' age , tumor size , uni - and multi-focality , expression of ER and PR , lymphovascular invasion , perineural invasion and lymph node metastasis . The only statistically different factor was P04626 REA over-expression , which was observed only in pleomorphic Q9Y4X3 REA ( P = 0.0073 ) . None of the 53 cases expressed CK5 / 6 , CK14 or CK17 ; and 51/53 cases expressed luminal markers CK8 and CK18 , and the two negative cases were both classic lobular carcinoma , with positivity for ER and PR . In conclusion , all 53 cases of Q9Y4X3 REA failed to show expression by any of the three basal CK markers , suggesting that very few Q9Y4X3 REA will demonstrate a basal phenotype when assessed by immunohistochemistry ( IHC ) . More studies are needed to investigate molecular classification in lobular carcinoma of the breast .

DB08916 SUB : A first-line treatment for selected patients with metastatic non-small-cell lung cancer . PURPOSE : The pharmacology , pharmacokinetics , clinical efficacy , safety , adverse effects , dosage and administration , and role in therapy of afatinib in the management of non-small-cell lung cancer ( NSCLC ) are reviewed . SUMMARY : DB08916 SUB ( Gilotrif , Boehringer Ingelheim ) is a novel oral tyrosine kinase inhibitor ( TKI ) recently approved for the first-line treatment of patients with NSCLC whose tumors are driven by activating mutations of genes coding for epidermal growth factor receptor ( P00533 REA ) . DB08916 SUB is also an inhibitor of a specific P00533 REA mutation ( T790M ) that causes resistance to first-generation P00533 REA - targeted TKIs in about half of patients receiving those drugs . The recommended dosage is 40 mg once daily . In a Phase III trial completed last year , patients with P00533 REA - mutated NSCLC who were treated with afatinib had a twofold higher response rate than those receiving standard combination chemotherapy ( 56 % versus 23 % ) and significantly longer progression-free survival ( 11.0 months versus 5.6 months ) . Other studies indicated that afatinib may offer advantages over standard chemotherapy for NSCLC in terms of enhanced symptom control and quality of life and is modestly effective in cases involving EGFRT 790M - related acquired resistance to the TKIs erlotinib and gefitinib . Among clinical trial participants , afatinib was generally well tolerated , with the most common grade I or II adverse events being diarrhea and rash or acne ; grade III or IV events were infrequent . CONCLUSION : DB08916 SUB is a novel TKI that is efficacious and well tolerated in patients with NSCLC associated with activating P00533 REA mutations , including cases involving the T790M resistance mutation . It has possible applications in other P00533 REA mutation - positive cancers .

Integration of P00533 REA inhibitors and conventional chemotherapy in the treatment of non-small-cell lung cancer . INTRODUCTION / BACKGROUND : Given the limited gains of traditional chemotherapy in improving outcomes in patients with advanced non-small-cell lung cancer ( NSCLC ) , recent research efforts have investigated the integration of targeted agents into the treatment algorithm . MATERIALS AND METHODS : Searches of PubMed and of recent results from key oncology congresses were performed to identify relevant articles and abstracts . Initial phase III trials combining the reversible epidermal growth factor receptor ( P00533 REA ) tyrosine kinase inhibitors ( TKIs ) gefitinib and erlotinib with platinum-based doublets as first-line therapy failed to demonstrate an overall survival advantage in unselected patients with NSCLC . However , in recent years , there has been substantial progress in understanding the determinants of response to P00533 REA TKI therapy , including the presence of activating P00533 REA mutations , which has been reflected in clinical trials specifically evaluating these patient populations . In addition , evidence suggesting potential mechanistic interference between concurrent P00533 REA TKIs and chemotherapy has also been observed , fueling interest in sequential or intermittent dosing . P00533 REA - targeted agents such as the multitargeted TKI vandetanib and the next-generation P00533 REA TKIs afatinib ( DB08916 SUB ) and PF00299804 are also under clinical investigation for the treatment of NSCLC , both alone and in combination with chemotherapy . CONCLUSIONS : Trials evaluating various regimens of P00533 REA - targeted agents and chemotherapy are planned and / or underway and will hopefully define the role of integrated therapy in NSCLC .

Potential of afatinib in the treatment of patients with P04626 REA - positive breast cancer . In the absence of treatment , overexpression of the human epidermal growth factor receptor 2 ( P04626 REA ) predicts a poor prognosis in breast cancer . In the last decade , monoclonal antibodies and small molecule tyrosine kinase inhibitors have significantly improved the outcome of P04626 REA - positive breast cancer patients . However , tumor resistance and toxicities often limit the use of these therapies . For this reason , there is a compelling need for further investigation of new targeted therapies , such as afatinib , an oral irreversible pan inhibitor of the epidermal growth factor receptor ( P00533 REA ) family . This compound covalently interacts with tyrosine kinase domains , which are deeply involved in signal transduction leading to cell proliferation and protection from apoptosis . DB08916 SUB has been studied in several Phase I clinical trials in advanced solid tumors . These trials have shown encouraging clinical activity and manageable side effects when afatinib is used either as a single agent or in combination with chemotherapy , with cutaneous adverse events and diarrhea being the most frequently observed toxicities . This review will focus on afatinib ' s clinical activity and will discuss ongoing clinical studies in P04626 REA - positive breast cancer patients . In the scenario of the different P04626 REA - targeted therapies , it will be important to define the best specific clinical and " molecular " setting for afatinib use , trying to identify predictors of resistance and response . Moreover , afatinib , which has the ability to cross the blood-brain barrier , could play a role in patients with brain metastases from breast cancer .

Forced dimerization increases the activity of Δ P00533 REA / EGFRvIII and enhances its oncogenicity . Delta epidermal growth factor receptor ( Δ P00533 REA ) , an in-frame deletion mutant of the extracellular ligand-binding domain , which occurs in about 30 % of glioblastoma , is a potent oncogene that promotes tumor growth and progression . The signaling of Δ P00533 REA is ligand-independent and low intensity , allowing it to evade the normal mechanisms of internalization and degradation by the endocytic machinery and hence is persistent . The basis of the oncogenic potential of Δ P00533 REA remains incompletely understood , including whether dimerization plays an important role in its signal and whether its oncogenic potential is dependent on its relatively low intensity , when compared with the acutely activated wild-type receptor . To examine these two important questions , we have generated a chimeric Δ P00533 REA that allows forced dimerization via domains derived from variants of the P62942 REA protein that are brought together by FK506 derivatives . Forced dimerization of chimeric Δ P00533 REA significantly increased the intensity of its signal , as measured by receptor phosphorylation levels , suggesting that the naturally occurring Δ P00533 REA does not form strong or stable dimers as part of its low level signal . Interestingly , the increased activity of dimerized , chimeric Δ P00533 REA did not promote receptor internalization , implying that reduced rate of endocytic downregulation of Δ P00533 REA is an inherent characteristic . Significantly , forced dimerization enhanced the oncogenic signal of the receptor , implying that the Δ P00533 REA is a potent oncogene despite , not because of its low intensity .

P00533 REA inhibition in lung cancer : the evolving role of individualized therapy . Non-small cell lung cancer ( NSCLC ) is the major cause of cancer-related deaths in the USA and worldwide . Most patients present with advanced disease , and treatment options for these patients are generally limited to platinum-based chemotherapy and a few targeted therapies . Targeted agents currently in use for NSCLC inhibit oncogenic receptor tyrosine kinase pathways , such as the epidermal growth factor receptor ( P00533 REA ) pathway . While current P00533 REA - targeted agents , including erlotinib and gefitinib , may result in dramatic responses , they demonstrate efficacy in only a fraction of patients , and resistance to these agents frequently develops . In order to select patients most likely to benefit from blockade of P00533 REA pathways , investigators have focused on identifying molecular correlates of response to anti - P00533 REA therapy . New strategies to minimize the risk of resistance to P00533 REA inhibition have been employed in the development of next-generation P00533 REA tyrosine kinase inhibitors , such as PF00299804 and DB08916 SUB ; these include irreversibility of target binding , inhibition of multiple P00533 REA family receptors , and / or simultaneous inhibition of P00533 REA and other oncogenic pathways .

Phase II Study of DB08916 SUB as Third-Line Treatment for Patients in Korea With Stage IIIB / IV Non-Small Cell Lung Cancer Harboring Wild-Type P00533 REA .

DB01590 MEN prolonged survival in transgenic mice with P00533 REA - driven lung tumors . DB01590 MEN is an orally administered P42345 REA inhibitor . The effect , and mechanism of action , of everolimus on lung cancers with an epidermal growth factor receptor ( P00533 REA ) mutation remain unclear . Four gefitinib-sensitive and - resistant cell lines were used in the present work . Growth inhibition was determined using the MTT assay . Transgenic mice carrying the P00533 REA L858R mutation were treated with everolimus ( 10 mg / kg / day ) , or vehicle alone , from 5 to 20 weeks of age , and were then sacrificed . To evaluate the efficacy of everolimus in prolonging survival , everolimus ( 10 mg / kg / day ) or vehicle was administered from 5 weeks of age . The four cell lines were similarly sensitive to everolimus . Expression of phosphorylated ( p ) P42345 REA and pS6 were suppressed upon treatment with everolimus in vitro , whereas the pAKT level increased . The numbers of lung tumors with a long axis exceeding 1mm in the everolimus-treated and control groups were 1.9 ± 0.9 and 9.4 ± 3.2 ( t-test , p < 0.001 ) , respectively . pS6 was suppressed during eve r olimus treatment . Although apoptosis and autophagy were not induced in everolimus-treated P00533 REA transgenic mice , angiogenesis was suppressed . The median survival time in the everolimus-treated group ( 58.0 weeks ) was significantly longer than that in the control group ( 31.2 weeks ) ( logrank test , p < 0.001 ) . These findings suggest that everolimus had an indirect effect on tumor formation by inhibiting angiogenesis and might be effective to treat lung tumors induced by an activating P00533 REA gene mutation .

Monitoring afatinib treatment in P04626 REA - positive gastric cancer with DB09150 and 89Zr - trastuzumab PET . We evaluated the ability of the PET imaging agent (8 9 ) Zr-trastuzumab to delineate P04626 REA - positive gastric cancer and to monitor the pharmacodynamic effects of the epidermal growth factor receptor ( P00533 REA ) / human epidermal growth factor receptor 2 ( P04626 REA ) tyrosine kinase inhibitor afatinib . METHODS : Using (8 9 ) Zr-trastuzumab , ( 18 ) F - DB09150 , or 3 ' - deoxy - 3 ' - ( 18 ) F-fluorothymidine ( ( 18 ) F - P17948 REA PET ) , we imaged P04626 REA - positive NCI-N 87 and P04626 REA - negative MKN 74 gastric cancer xenografts in mice . Next , we examined the pharmacodynamic effects of afatinib in NCI-N 87 xenografts using (8 9 ) Zr-trastuzumab and ( 18 ) F - DB09150 PET and comparing imaging results to changes in tumor size and in protein expression as monitored by Western blot and histologic studies . RESULTS : Although ( 18 ) F - DB09150 uptake in NCI-N 87 tumors did not change , a decrease in (8 9 ) Zr-trastuzumab uptake was observed in the afatinib-treated versus control groups ( 3.0 ± 0.0 percentage injected dose per gram ( % ID / g ) vs . 21.0 ± 3.4 % ID / g , respectively ; P < 0.05 ) . (8 9 ) Zr-trastuzumab PET results corresponded with tumor reduction , apoptosis , and downregulation of P04626 REA observed on treatment with afatinib . Downregulation of total P04626 REA , phosphorylated ( p ) - P04626 REA , and p - P00533 REA occurred within 24 h of the first dose of afatinib , with a sustained effect over 21 d of treatment . CONCLUSION : DB08916 SUB demonstrated antitumor activity in P04626 REA - positive gastric cancer in vivo . (8 9 ) Zr-trastuzumab PET specifically delineated P04626 REA - positive gastric cancer and can be used to measure the pharmacodynamic effects of afatinib .