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fredag 2 februari 2018

BET estäjät, uutta syöpälääkettä kliinisissä kokeissa

Biomedisiinisen kirajston hyllyllä oleva  uusi syöpäterapiasta kertova kirja maintisi näitä BETi lääkkeitä olevan kliinisissä kokeissa, muutama on kliinisessä faasissa III, ja sitten on  II- ja I- faasissakin useita valmisteita. (Löysin tämän aiheen etsiessäni TRIM-proteiinista tietoa)
 Siitä kertoi muutamat rivit sellaisessa artikkelissa, joka  kuvasi BET-inhibiittoreita_ Shaokun Shu et Kornelia Polyak: BET Bromodomain Proteins as Cancer Therapeutic targets. 

https://en.wikipedia.org/wiki/BET_inhibitor

BET-estäjät ovat  luokka  antisyöpälääkkeitä, immuniosuppressiivisia ja muitakin vaikutuksia niillä  on kliinisten kokeiden perusteella  ollut. USA:ssa ja Euroopassa tehdään näitä kokeita Nämä molekyylit sitoutuvat reversibelisti eli palautuvasti bromodomaaniin BET-proteiineissa BRD2, BRD3, BRD4 ja BRDT. BET on lyhennys sanoista Bromodomain and  Extra-Terminal motif-proteins, joita yllämainitut 4 ovat. 
Sisältö
Contents
  • 1 Discovery and development
  • 2 Mechanism of action in cancer
  • 3 Use in other applications
  • 4 Specific BET inhibitors
  • 5 See also
  • 6 References
  •  

  • BET-inhibiittorien löytäminen ja kehittely , Discovery and development

     Tienodiatsepiini-BETi  molekyylit keksi  tiedemiehet Yoshitomi Pharmaceuticals  yhtiössä, joka nykyisin on  Mitsubishi Tanabe Pharma. Tämä tapahtui  1990-luvun varhaisvaiheissa. Havaittiin niitten olevan anti-inflammatorisia ja  antisyöpä agensseja. Niistä ei pitkään tiedetty sen enempää, kunnes julkaistiin tieto JQ1 (tienotriazolodiatsepiinin)  käytöstä  eräässä syöpätyypissä (NUT midline carcinoma) ja  I-Bet 762:n käytöstä sepsiksessä. Sen jälkeen on kuvattu useitakin  molekyylejä, jotka kykenevät kohdentumaanBET- bromodomaaniin.
    On kuvattu sellaisiakin BET-inhibiittoreita, jotka pystyvät tekemään eron BET-proteiinien  ensimmäisen BD1 ja toisen BR2  bromodomaanin kesken. Muta ei ole vielä  löydetty yhtään BETi;ä joka voisitehdä eron   neljän BET-perheen jäsenen kesken.  Vain tieteellisessä tutkimuksessa  on voitu kodhentaa yksittäiseen BET-proteiiniin mutatoimalla niitä  herkemmiksi Jq1/I-Bt762:LLE.

    • Thienodiazepine BET inhibitors were discovered by scientists at Yoshitomi Pharmaceuticals (now Mitsubishi Tanabe Pharma) in the early 1990s, and their potential both as anti-inflammatories and anti-cancer agents noted.[3][4] However, these molecules remained largely unknown until 2010 when both the use of JQ1 in NUT midline carcinoma[5] and of I-BET 762 in sepsis were published.[6] Since this time a number of molecules have been described that are capable of targeting BET bromodomains.[7] BET inhibitors have been described that are able to discriminate between the first and second bromodomains of BET proteins (BD1 vs BD2). However, no BET inhibitor has yet been described that can reliably distinguish between BET family members (BRD2 vs BRD3 vs BRD4 vs BRDT).[8] Only in the research context has targeting individual BET proteins been achieved by mutating them to be more sensitive to a derivative of JQ1 / I-BET 762.[9]

    Miten BETi toimii syövässä? Mechanism of action in cancer

      Heräsi kiinnostus BEt-inhibiittoreita kohtaan, kun oli havaittu BET-geenien BRD 3 ja BRD4 kormosomaalisten translokaatioitten  käynnistävän patogeneesin  eräässä  harvinaisessa syöpämuodossa. Jatkotutkimuksissa  löytyi  riippuvuutta  BET-proteiinista BRD4 eräissä  akuutin myeloisen leukemian muodoissa , multippelissa myelomassa ja akuutissa lymfoblastisessa leukemiassa- ja nämä syövät olivat  herkkiä BET-inhibiittoreille.
    BRD2 ja BRD3 ovat toiminnallisesti redundantteja ja ne voivat olla tärkeämpiä terapeuttisina  kohteina, mitä ollaan  arvioitu niistä kokeista, joissa  vähennetään  jokasen  BET-proteiinin osuus erikseen. Tuoreet tutkimukset ovat osoittaneet, että kombinaatioterapiassa käyttäen BETi voi olla  hyvä keino voittaa muita kohdennetuja terapioita vastaan kehittynyt resistenssi. Esim BETi ja gammasekretaasi-inhibiittori kombinoituna  Akuutissa T-lymfoblastileukemiassa  ja  BETi kombinoituna
    RAF-inhibiittoriin (vemurafenib)  RAF-inhibiittorille resistentissä melanoomassa, jossa on BRAFV600E mutaatio.

    • Interest in using BET inhibitors in cancer began with the observation that chromosomal translocations involving BET genes BRD3 and BRD4 drove the pathogenesis the rare cancer NUT midline carcinoma. Subsequent research uncovered the dependence of some forms of acute myeloid leukemia,[10][11] multiple myeloma and acute lymphoblastic leukemia[12] on the BET protein BRD4, and the sensitivity of these cancers to BET inhibitors. In many cases, expression of the growth promoting transcription factor Myc is blocked by BET inhibitors.[13][14][15] BRD2 and BRD3 are functionally redundant and may be more important as therapeutic targets than is appreciated in studies depleting each BET protein individually.[16] Recent studies also showed that BET inhibitors can be instrumental in overcoming resistance to other targeted therapies when used in combination therapies. Examples include use of BET inhibitors in combination with γ-secretase inhibitors for T cell acute lymphoblastic leukemia and RAF-inhibitor (vemurafenib) for RAF-inhibitor resistant melanomas carrying the BRAFV600E mutation.[17][18]

    Muita käyttösovelluksia. Use in other applications

Hiirimallissa on todettu BET-inhibiittorin  ehkäisevän sepsiskuolemaa,  heikentävän autoimmuniteettia ja  vähentävän  yliaktiivin immunovasteen aiheuttamia vaurioita keuhkoissa. Prekliinisissä tutkimuksissa on osoitettu tehokkuutta  sovelluksissa, jotka vaativat  kroonista  lääkkeenantoa ( sydämen toiminnan pettäminen ja  miehen kontraseptio) .  Varhaisten ihmiskokeiden mukaan on  merkisevää toksisuutta  havaittu, mikä ilmenee trombosytopeniana. Nämä lääkeaineet todennäkösesti  omaavat vahvoja immunomodulatorisia  vaikutuksia. On vielä epäselvää, missä rajoissa tulee olemaan  turvallisia toteutettavissa olevia  sovelluksia  näille molekyyleille.
Tässä on nyt aika pitkä sitaatti, mutta otan talteen koska  näyttää olevan  tärkeä lisä tulossa  syöpälääkkeisiin. 2.2. 2018

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TRIM, Tripartite Motif -proteiinit n. 80 jäsentä perheessä

Vuosia sitten  jonkin (retroviruspandemian aikaan luin luonnollisesta ( aina valmiina olevasta)  immuniteetista  ja siinä yhteydessä TRIM-proteiiniperheestä. Käänsin vihkooni tietoja artikkelista (2008) :
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433745/

 Vähän aika sitten hain TRIM-geenien sijainnin kromosomistossa. Sitä on aika laajalti eri kromosomeissa. satakunta geeniä, osa pseudogeenejä.

Tänään kirjastossa  päätin katsoa sen uuden Cancer-kirjan  indeksistä APOBECin ja TRIMin , kun ne näkyy kuuluvan onkologiankin piiriin.
 ASIASTA TRIM33 mainittiin  sivulla  muutamalla senttimetrillä  colon carcinoma-  yhteydessä. Tästä TRIM33  proteiinista ei mainittu em. artikkelissa.

Loss of Tripartite Motif- containing protein 33, a chromatin associated E3 ubiquitin ligase, was identified  to confer resistance to BETi ( tästä erikseen), based on shRNA-based genetic screen (2016).

TRIM33 silencing reprograms cancer cells to a more resistant state
by  these mechanisms:
1) TRIM33 loss maintains MYC-expression following BETi treatment.
2) silencing enhances TGFbetaR expression and signaling.


Katsoin nyt kotiin tultua PubMed hakulaitteesta, mikä on TRIM-  proteiiniperheen asema  tutkimuskentillä maailmassa ja  löysin tuoreen päivityksen:

TRIM33 geeni on kr. 1p13.2 kohdalla. 
 (TRIM-proteiineja tunnetaan nykyisin noin 80) .
Tämä mainittiin colon carsinoman yhteydessä.  Se säätyy siinä  ylös .

http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006787

  • Mikä on uusinta tietoa TRIM-proteiineista?

PLoS Pathog. 2018 Feb 1;14(2):e1006787. doi: 10.1371/journal.ppat.1006787. eCollection 2018 Feb.
 TRIM proteins: New players in virus-induced autophagy.
Sparrer KMJ1, Gack MU1.
PMID:29389992
DOI:10.1371/journal.ppat.1006787
  •  Otan tähän sitaatin. 

Role of autophagy during viral infection

Autophagy is an evolutionarily conserved and intricately regulated cellular process in which damaged or aggregated proteins, organelles, and pathogen-derived components are engulfed by double-membrane structures, termed autophagosomes, and targeted for lysosomal degradation [1].
 The autophagic process consists of distinct phases that include nucleation, autophagosome formation, selection of cargo, autophagolysosomal fusion, and cargo degradation.
 Autophagy induction is governed by a set of kinases, including Unc-51-like autophagy activating kinase 1 (ULK1), that activate autophagy via assembly of an essential Beclin-1-containing complex. Conversely, the mammalian target of rapamycin (mTOR) is an important negative regulator of autophagy initiation. A hallmark of autophagic flux is the conversion of the microtubule-associated protein light chain 3B (LC3B) from a cytosolic form to a phosphatidylethanolamine-lipidated,(PE)-lipidated membrane-associated form decorating autophagosomes in punctae-like structures.
 Several forms of autophagy have been identified, including starvation-triggered autophagy, which is a nonspecific autodigestive response, and selective autophagy, in which “tagged” cargos are specifically recognized by sequestosome1 (SQSTM1)-like receptors, such as p62/SQSTM1 or nuclear dot protein 52 (NDP52) [2]. As such, autophagy has been implicated in multiple cellular processes, including stress adaptation, protection against inflammation, neurodegeneration, and antimicrobial activities [3].
Autophagy is induced upon infection by many different viruses from diverse families, yet the impact of the autophagic host response on viral replication is highly virus and cell-type specific [3]. Some viruses or their components are degraded by autophagy, which limits virus replication and thus serves as an antiviral defense pathway.
Additionally, autophagosomes can capture viral components and expose pathogen-associated molecular patterns (PAMPs) to innate immune sensors (e.g., Toll-like receptors) upon fusion with endosomes, ultimately promoting innate immune recognition and cytokine-mediated host defenses [4]. Among the viruses sensitive to autophagy-mediated clearance are herpes simplex virus type 1 (HSV-1), Sindbis virus (SINV), and human immunodeficiency virus type 1 (HIV-1).
On the other hand, viruses like encephalomyocarditis virus (EMCV), dengue virus, and Zika virus subvert autophagy to promote their replication, and inhibition of autophagic flux suppresses the replication of these viruses [5].
Given the important antiviral and proviral roles of autophagy, it is not surprising that many viruses are equipped with sophisticated mechanisms to modulate autophagy in the infected host cell.
 For example, EMCV induces autophagy through ER stress via its nonstructural proteins 2C and 3D [6],
whereas the γ34.5 protein of HSV-1 suppresses autophagy by interacting with Beclin-1 [7].
Furthermore, the M2 protein of influenza A virus (IAV) modulates autophagy by sequestering LC3B to non-autophagosomal membranes, thereby facilitating virion stability [8].

Emerging role of TRIM proteins in virus-induced autophagy

A major family of antiviral molecules with approximately 80 members in humans are tripartite motif (TRIM) proteins, which are characterized by the presence of an N-terminal Really Interesting New Gene (RING) domain, one or two B-boxes, and a coiled-coil domain [9].
While most TRIM proteins encode ubiquitin E3 ligase activity conferred by the RING domain, distinct C-terminal domains allow for specific protein—protein interactions or harbor additional enzymatic activities.
 Whereas TRIM proteins are widely recognized as important antiviral restriction factors or modulators of signaling pathways leading to the induction of antiviral or proinflammatory cytokines, such as type I interferons (IFNs), their roles in other cellular pathways are less well established [9].
A recent series of studies showed that autophagy and antiviral cytokine responses are intricately interconnected [3,4].
Several key molecules implicated in IFN induction are also important regulators of the autophagy pathway.
For example, autophagy-related 5 (Atg5)-Atg12 and the nucleotide-binding oligomerization domain (NOD)-like receptor family member X1 (NLRX1) dually regulate virus-induced type I IFN production and autophagy [10,11].
Furthermore, the immunoregulatory kinase TANK-binding kinase 1 (TBK1), which is well known to regulate IFN induction through phosphorylation of IFN regulatory factor 3 and 7 (IRF3/7), also promotes autophagic clearance by phosphorylating the autophagy receptor p62 [12–14].

Interestingly, recent studies demonstrated that several TRIM proteins are key regulators of both viral- and non-viral-induced autophagy, further supporting the intricate intertwining of IFN-mediated innate immunity and autophagy. In a cDNA screen, 31 out of 61 tested TRIM proteins triggered green fluorescent protein (GFP)-LC3B puncta formation, indicative of autophagy induction [14]. An independent study measuring the effect of small interfering RNA (siRNA)-mediated depletion of TRIM proteins showed that autophagy triggered by treatment with pp242 (an mTOR inhibitor) was dependent on 21 TRIM proteins [15]. Another study found 24 TRIM proteins to be essential for IFNγ-induced autophagy [16]. Moreover, a targeted TRIM RNAi screen examining the effect of silencing individual TRIMs on autophagy induction by either EMCV, IAV, or HSV-1 infection, revealed that several TRIM proteins regulate autophagy induced by a particular virus, for example, only during infection with HSV-1 but not IAV or EMCV [14].
 Intriguingly, TRIM proteins regulating innate immune pathways triggered by specific viruses (e.g., TRIM25 activating the viral RNA sensor retinoic acid-inducible gene-I (RIG-I) and thereby IFN induction in response to IAV; TRIM56 regulating stimulator of interferon genes (STING) signaling in response to HSV-1 infection) were also essential for autophagy induction by those same viruses. This suggests that the role of these TRIM proteins in autophagy during viral infection is tightly interconnected with their functions in IFN-mediated antiviral immunity. Moreover, some TRIM proteins (e.g., TRIM21, TRIM23, and TRIM41) were found to be required for autophagy induction by several viruses [14], suggesting that these TRIM proteins are core components of the autophagy machinery, or act at a common step of the autophagy induction pathway.
At least two different mechanisms of action have been proposed for TRIM proteins acting in antiviral autophagy. Some TRIM proteins act as specific cargo receptors that directly recognize viral components and target them for degradation by autophagy. Other TRIM proteins regulate the activity of key signaling proteins involved in different steps in the autophagy pathway (Fig 1).

Fig 1. TRIM proteins modulate virus-induced autophagy.
TRIM proteins have at least two different modes of action during virus-induced autophagy. They can act as autophagy receptors that specifically recognize and target viral components for autophagolysosomal degradation (exemplified here by TRIM5α [A]), or they regulate the activity of key autophagy molecules (exemplified here by TRIM23 [B]). (A) After infection of a cell with HIV-1, TRIM5α binds to the capsid of HIV-1, inducing premature capsid disassembly and virus restriction. Both proteasomal (not illustrated) and autophagosomal degradative mechanisms reportedly play a role in viral capsid protein (p24) degradation. For autophagic clearance, the p24-TRIM5α complex is recruited to nucleated autophagosomes, where TRIM5α induces autophagy in a Beclin-1- and ULK1-dependent manner. (B) Upon infection by diverse viral pathogens (e.g., HSV-1, SINV, adenovirus), the E3 ligase activity of TRIM23 is induced, which leads to atypical K27-linked auto-polyubiquitination of its C-terminal ARF domain. This modification triggers GTP-GDP cycling of the TRIM23 ARF GTPase, which, upon binding of TRIM23 to TBK1, induces dimerization and trans-autophosphorylation of TBK1 and, thereby, activation of the kinase. Activated TBK1 then phosphorylates the autophagy receptor p62 at specific serine residues, which allows p62 to recognize specific cargos, such as viral proteins, ultimately triggering their degradation via the lysosome. ARF, ADP ribosylation factor; Auto-K27-polyUb, auto-K27-linked polyubiquitination; E3, E3 ubiquitin ligase; GTP-GDP, guanosine triphosphate-guanosine diphosphate; HSV-1, herpes simplex virus type 1; P, phosphorylation; SINV, Sindbis virus; TBK1, TANK-binding kinase 1; TRIM, tripartite motif; ULK1, Unc-51-like autophagy activating kinase 1; Ub, ubiquitin.

TRIM proteins acting in cargo recognition

The concept of TRIM proteins acting as “autophagy receptors” by recognizing viral proteins as cargo has been most well characterized for TRIM5α, which was initially discovered as an antiviral restriction factor that recognizes the HIV capsid protein [17]. While Old World monkey TRIM5α is able to recognize HIV-1 capsids, the human TRIM5α fails to do so. Human TRIM5α, however, still retains the ability to bind to certain murine retroviral capsids, demonstrating species-specific restriction. Several different mechanisms have been proposed for TRIM5α-mediated retroviral restriction [18]. Recognition of the HIV-1 capsid by the SPRY domain of TRIM5α leads to premature capsid disassembly and degradation. Capsid degradation was thought to be mediated by the proteasome, but more recently, TRIM5α has been reported to initiate autophagy through recruitment of two key components of the autophagy machinery—ULK1 and Beclin-1—thereby eliciting autophagy-dependent degradation of the HIV capsid [15] (Fig 1). It has been proposed that formation of the TRIM5α lattice around the capsid may trigger autophagy-mediated restriction of HIV-1 infection [19]. However, other data suggested that retroviral restriction by TRIM5α can still be observed in systems lacking key autophagic components [20], implying that autophagy is not the sole contributor to TRIM5α’s restrictive phenotype and that nondegradative mechanisms likely contribute to retrovirus restriction by TRIM5α. A recent screen showed that silencing of TRIM5α also abrogated autophagy induction by HSV-1 infection [14], suggesting that the role of TRIM5α during autophagy is not limited to retroviral infection. Future studies will need to establish the role of TRIM5α in autophagy during infection by other viral pathogens. Furthermore, the relative contribution of autophagy as compared to other degradative pathways to TRIM5α-mediated retroviral restriction will require further investigation. Finally, although a role for several other TRIM proteins, such as TRIM20 and TRIM21, in autophagy cargo recognition has been reported [16], the relevance of those TRIM proteins in virus-induced autophagy remains to be determined, opening up exciting new avenues of research in virology.

TRIM proteins functioning as regulators of the autophagy machinery

Independent screening approaches identified several TRIM proteins that play essential roles in both nonviral and viral-induced autophagy, suggesting a key role for these TRIMs in the autophagic process [14–16]. The precise molecular mechanism for most of these TRIMs has not yet been elucidated; however, recently, the role of TRIM23 during virus-induced autophagy was characterized in detail. Silencing or gene targeting of TRIM23 abrogated autophagic flux triggered by a broad range of viral pathogens, which correlated with increased replication of the autophagy-sensitive viruses SINV, adenovirus, and HSV-1, suggesting that TRIM23 mediates virus clearance by autophagy [14]. TRIM23 is unique among TRIM proteins in that it exhibits two enzymatic functions: E3 ubiquitin ligase activity in the RING domain, as most TRIM proteins, and GTPase activity at its C-terminal ARF domain. Thus, TRIM23 can be considered as a fusion protein of a classical tripartite motif and a member of the ARF protein family, which are small (about 20 kDa) GTPases known to modulate cellular membranous processes. Interestingly, the enzymatic activities of TRIM23 are intricately connected and both are required for autophagy induction. Using its RING E3 ligase activity, TRIM23 auto-ubiquitinates its ARF domain, and this posttranslational modification is necessary for TRIM23-mediated autophagic flux and antiviral activity. In-depth biochemical characterization revealed that the ARF domain of TRIM23 is modified by atypical K27-linked polyubiquitin chains, which activate the cycling activity of its GTPase (Fig 1). Mechanistic studies showed that GTP to GDP cycling of TRIM23 facilitates TBK1 dimerization and trans-autophosphorylation and, thereby, activation of the kinase. TBK1 then proceeds to phosphorylate p62 to induce selective autophagy, ultimately promoting viral clearance [14]. These results indicated that the TRIM23-TBK1-p62 axis is important for autophagy-mediated antiviral defense. As both TRIM23 and TBK1 play prominent roles also in the antiviral IFN response, future studies will need to determine the relative contribution of their autophagy- and IFN-regulatory functions to virus restriction. Furthermore, the impact of TRIM23 on the replication of viruses known to usurp autophagy for their efficient replication warrants further investigation.

Concluding remarks and perspectives

The recent discovery of the role of TRIM proteins in viral autophagy opens up an entirely new area of research in antiviral intrinsic immunity. Whereas the mechanism of autophagy regulation is unknown for most TRIM proteins, it is becoming clear that some TRIM proteins act as receptors recognizing viral molecules, while others are critical components of the autophagy machinery that mediates virus clearance. Although most viruses induce autophagy, the viral signals that trigger autophagy as well as the upstream signaling pathways initiated upon virus-induced autophagy are not very well defined yet. Furthermore, as key autophagy proteins are known to be targeted by viral pathogens in order to evade or manipulate autophagic flux, it is likely that autophagy functions of TRIM proteins are targeted by specific viruses as well. Along these lines, the central role of TBK1 in IFN-mediated immunity is antagonized by a myriad of viral pathogens; however, it remains to be determined whether viral evasion strategies also target TBK1’s activity in autophagy-mediated antiviral defense. Moreover, many proteins known to play key roles in antiviral cytokine responses (including TRIMs and TBK1) have recently emerged as important regulators of autophagy. While some TRIM proteins regulate autophagy-mediated clearance of viral components, others direct the destruction of host innate immune components (such as inflammasome proteins or IRF3) via autophagy. Thus, it will be fascinating to investigate the dual roles of these molecules in both autophagy and cytokine responses during viral infection. Future discoveries in the area of autophagy-mediated host defenses by TRIM proteins may unveil new opportunities for therapeutic intervention in viral infectious diseases.

References


https://doi.org/10.1371/journal.ppat.1006787.g001
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torsdag 1 februari 2018

PubMed haku HER3 geeni

Haku HER3 Homo sapiens antaa 48  geeniä klusterina ja siitä joukosta  löytää HER 3 (Kromosomi 12) ,HER1 (Kromosomi7) ,  HER2 (kromosomi 2) ,  tässä yhteydessä olennainen mielestäni PTEN (kromosomi 10) , AKT (kromosomi 14), MTOR (kromosomi 1) , PI3KCA (Kromosomi 3)  ainakin. Vaihtoehtoisnimistä löytyy nämä HER- geenit.

Search results

Items: 1 to 20 of 48

  • Showing Current items.
Name/Gene IDDescriptionLocationAliasesMIM
ID: 2065		erb-b2 receptor tyrosine kinase 3 [Homo sapiens (human)]Chromosome 12, NC_000012.12 (56080025..56103507)ErbB-3, HER3, LCCS2, MDA-BF-1, c-erbB-3, c-erbB3, erbB3-S, p180-ErbB3, p45-sErbB3, p85-sErbB3190151
ID: 1956		epidermal growth factor receptor [Homo sapiens (human)]Chromosome 7, NC_000007.14 (55019032..55207338)ERBB, ERBB1, HER1, NISBD2, PIG61, mENA131550
ID: 2064		erb-b2 receptor tyrosine kinase 2 [Homo sapiens (human)]Chromosome 17, NC_000017.11 (39688084..39728662)CD340, HER-2, HER-2/neu, HER2, MLN 19, NEU, NGL, TKR1164870
ID: 207		AKT serine/threonine kinase 1 [Homo sapiens (human)]Chromosome 14, NC_000014.9 (104769349..104795743, complement)AKT, CWS6, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA164730
ID: 672		BRCA1, DNA repair associated [Homo sapiens (human)]Chromosome 17, NC_000017.11 (43044295..43125483, complement)BRCAI, BRCC1, BROVCA1, FANCS, IRIS, PNCA4, PPP1R53, PSCP, RNF53113705
ID: 3576		C-X-C motif chemokine ligand 8 [Homo sapiens (human)]Chromosome 4, NC_000004.12 (73740506..73743716)GCP-1, GCP1, IL8, LECT, LUCT, LYNAP, MDNCF, MONAP, NAF, NAP-1, NAP1146930
ID: 5728		phosphatase and tensin homolog [Homo sapiens (human)]Chromosome 10, NC_000010.11 (87863438..87971930)10q23del, BZS, CWS1, DEC, GLM2, MHAM, MMAC11, PTENbeta, TEP1, PTEN601728
ID: 4233		MET proto-oncogene, receptor tyrosine kinase [Homo sapiens (human)]Chromosome 7, NC_000007.14 (116672359..116798386)AUTS9, DFNB97, HGFR, RCCP2, c-Met164860
ID: 3084		neuregulin 1 [Homo sapiens (human)]Chromosome 8, NC_000008.11 (31639222..32771716)ARIA, GGF, GGF2, HGL, HRG, HRG1, HRGA, MST131, MSTP131, NDF-IT2, SMDF, NRG1142445
ID: 2475		mechanistic target of rapamycin kinase [Homo sapiens (human)]Chromosome 1, NC_000001.11 (11106531..11262551, complement)FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS601231
ID: 5290		phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [Homo sapiens (human)]Chromosome 3, NC_000003.12 (179148114..179240093)CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-alpha, p110-alpha171834
ID: 675		BRCA2, DNA repair associated [Homo sapiens (human)]Chromosome 13, NC_000013.11 (32315480..32399672)BRCC2, BROVCA2, FACD, FAD, FAD1, FANCD, FANCD1, GLM3, PNCA2, XRCC11600185
ID: 1026		cyclin dependent kinase inhibitor 1A [Homo sapiens (human)]Chromosome 6, NC_000006.12 (36676460..36687339)CAP20, CDKN1, CIP1, MDA-6, P21, SDI1, WAF1, p21CIP1116899
ID: 3480		insulin like growth factor 1 receptor [Homo sapiens (human)]Chromosome 15, NC_000015.10 (98648539..98964530)CD221, IGFIR, IGFR, JTK13147370
ID: 4780		nuclear factor, erythroid 2 like 2 [Homo sapiens (human)]Chromosome 2, NC_000002.12 (177230303..177265131, complement)HEBP1, IMDDHH, NRF2600492
ID: 2100		estrogen receptor 2 [Homo sapiens (human)]Chromosome 14, NC_000014.9 (64226712..64338631, complement)ER-BETA, ESR-BETA, ESRB, ESTRB, Erb, NR3A2601663
ID: 4582		mucin 1, cell surface associated [Homo sapiens (human)]Chromosome 1, NC_000001.11 (155185824..155192915, complement)ADMCKD, ADMCKD1, CA 15-3, CD227, EMA, H23AG, KL-6, MAM6, MCD, MCKD, MCKD1, MUC-1, MUC-1/SEC, MUC-1/X/ZD, PEM, PEMT, PUM, MUC1158340
ID: 3688		integrin subunit beta 1 [Homo sapiens (human)]Chromosome 10, NC_000010.11 (32900318..32958365, complement)CD29, FNRB, GPIIA, MDF2, MSK12, VLA-BETA, VLAB135630
ID: 5595		mitogen-activated protein kinase 3 [Homo sapiens (human)]Chromosome 16, NC_000016.10 (30114105..30123309, complement)ERK-1, ERK1, ERT2, HS44KDAP, HUMKER1A, P44ERK1, P44MAPK, PRKM3, p44-ERK1, p44-MAPK601795
ID: 238		ALK receptor tyrosine kinase [Homo sapiens (human)]Chromosome 2, NC_000002.12 (29192774..29921611, complement)CD246, NBLST3105590

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Sama valmiste Ruotsissa. Peruzumab


HUOM. Kommenttini

http://www.onkologiisverige.se/tag/pertuzumab/ 
Tästä löytyy ruotsalaisten  onkologien lausunto Perjetalääkkeestä jo vuodelta
2016.
 Otan siitä sitaatin seuraavaan: 

2016 

NT-rådets yttrande om pertuzumab vid bröstcancer

Av SKL
15 Mar 2016
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NT-rådet rekommenderar landstingen att använda Perjeta neoadjuvant vid lokalt avancerad HER2-positiv bröstcancer men avstå från att generellt använda Perjeta neoadjuvant vid mindre stadier av bröstcancer, utanför kliniska prövningar.

2014

NYA LÄKEMEDEL mot ER-positiv bröstcancer

Av ANDERS NYSTRAND, FOTO: BOSSE JOHANSSON
2 Dec 2014
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Nya läkemedel mot den intracellulära signalvägen PI3K/Akt/mTOR kan komma att bli värdefulla tillskott till behandlingsarsenalen mot östrogenberoende bröstcancer.
 Med hjälp av alltmer sofistikerade genetiska tester kan patienternas prognos säkrare bedömas, vilket bland annat kan minska behovet av cytostatikabehandling.
Det framgick av ett satellitsymposium som hölls i anslutning till SOTA Breast Cancer Meeting i Stockholm i början av oktober.
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Guardian kertoo erään lääkeaineen käyttöindikaatiosta

 https://www.chugai-pharm.co.jp/hc/Satellite?blobcol=urldata&blobkey=id&blobtable=MungoBlobs&blobwhere=1396858649959&ssbinary=true
 Netistä löytyy kuvia näistä  HER2-signalointitien inhibitioperiaatteesta solutasossa.
Eräs näistä  immunomodulaattorilääkkeistä on osoitautunut olevan elämänikää pidentävä hyvin vaikeassa rintasyövässä ja tästä Guardian kertoo artikkelsisa. Lääke on  Rochen  valmiste.

Sitaatti Guardian lehdestä.  Huomaa Rutosin FASS luettelo.  Näitä vaikuttavia elämänpidentäjiä koetetaan kuumeisesti maailmassa  löytää. Vähä vähältä löytyy jokin pieni kapea elämänlanka. 

Nice approves life-extending drug for patients with incurable breast cancer

NHS doctors in England able to prescribe pertuzumab after price cut agreed with maker
drug that can give women suffering from incurable advanced breast cancer an extra 16 months of life has been approved for general use in the NHS in England after a price cut was negotiated with the manufacturer.
The decision by Nice, the National Institute for Health and Care Excellence, to give the green light for NHS doctors to use pertuzumab, sold under the brand name of Perjeta by the Swiss drug company Roche, was enthusiastically welcomed by breast cancer charities.







Baroness Delyth Morgan, chief executive of Breast Cancer Now, said the benefits of the drug for patients with the aggressive form known as Her2-positive breast cancer were extraordinary.
“This is the best news patients with Her2-positive breast cancer and their doctors could have hoped for,” she said. “Perjeta is a truly life-changing drug and we are absolutely delighted and relieved that Nice has finally been able to recommend it for routine NHS use in England.”
Perjeta had been too expensive to be considered for NHS use by Nice, which approves or rejects drugs on the basis of cost-effectiveness. But recently NHS England has begun to intervene with the manufacturers over the fraught issue of the prices of new drugs. Last November, it announced it had struck a deal with Roche.
“While a long time coming, we’re thrilled that tough negotiation and flexibility by NHS England and Nice, and the willingness of Roche to put patients first and compromise on price, has again ensured thousands of women can be given more time to live,” said Morgan.
But she was concerned that women with metastatic breast cancer – which has spread to other parts of the body and is incurable – would not get the drug in other parts of the UK.








“While Perjeta will now continue to be the gold standard of care in England, it has never been routinely available in Scotland, Wales or Northern Ireland. This is the most effective breast cancer drug in years and we must urgently see equality in access for NHS patients across the UK,” she said. She called for other countries to negotiate a deal with Roche.
Roche said the decision ends several years of uncertainty over a drug that is approved for use in 19 other European countries including France, Italy and Spain. “We are extremely pleased that due to the collaborative approach Roche, NHS England and Nice have taken, Perjeta will now be routinely funded on the NHS for eligible patients with advanced breast cancer,” said Richard Erwin, general manager of Roche Products Ltd.
Nice decided not to approve a second drug for advanced breast cancer, fulvestrant, sold under the brand name Faslodex, which slows its progress by suppressing the hormones that feed it. Samia al Qadhi, chief executive of charity Breast Cancer Care, said “This closed door will be a blow to many diagnosed with the cruel disease.”
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HUOM. Tämä Rochen valmiste   kuuluu suureen lääkeryhmään, josta Ruotsiss on myös FASS-luettelo. sen hierarkiasta tässä on osittainen  sitaatti. Sen koodinumero  omassa ryhmässään on L01XC13, ja netistä voi löytää siitä  ruotsalaista asennoitumista tähän valmisteeseen.








HUOM. Kommenttini
http://www.onkologiisverige.se/tag/pertuzumab/
Tästä löytyy ruotsalaisten  onkologien lausunto Perjetalääkkeestä jo vuodelta
2016. otan siitä sitaatin seuraavaan .
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