Abnormalities Of The Jak Stat Pathway Possible Treatments Biology Essay

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ALK+ALCLs (Anaplastic Lymphoma Kinase+ Anaplastic Large Cell Lymphoma) are relatively uncommon but research in this form of neoplasm presents the opportunity to treat more common forms of cancer. This neoplasm is characterized by the fusion of the NPM (Nucleophosmin) and ALK genes to form NPM-ALK. The progression of the cancer is controlled by signalling, in this article I will concentrate on the jak-stat pathway (Janus Activated Kinase-Signal Transducing and Activator of Transcription) in oncogenesis. The jak-stat pathway controls cell proliferation, cell survival and apoptosis. In cancer there is a continued jak activation causing an activation of stats, continuing the signalling pathway and leading to a constant cell proliferation and increased tumour cell survival aiding oncogenesis. With time and more research into this topic, more effective and specific treatments will be produced to treat not only ALK+ALCLs but possibly other forms of neoplasms.


The Jak-Stat pathway is involved in intracellular signalling and it is required for cell proliferation and haematopoiesis. There are 4 Jaks (Janus Activated Kinases) named Jak1, Jak2, Jak3 and Tyk2[1] (non-receptor protein Tyrosine Kinase-2). Stats (Signal Transducer and Activator of Transcription) become activated after recruitment to an activated receptor complex. There are 7 Stats called Stat1, Stat2, Stat3, Stat4, Stat5a, Stat5b and Stat6. Often in cancer this pathway can be disrupted by a mutation. The Jak-Stat pathway is activated by the binding of interferon alpha (IFN-a) to a cell surface receptor.

ALK+ALCLs (Anaplastic Large Cell Lymphomas) are defined as carrying a t(2;5)(p23;q35) chromosomal transformation. This means that the 3' section of ALK (Anaplastic Lymphoma Kinase) from chromosome 2 is fused onto the 5' part of NPM (Nucleophosmin) on chromosome 5 to form the NPM-ALK fusion gene which is oncogenic. They also have CD30 expression, a sinusoidal infiltrative pattern and a t-cell immunophenotype.


Anaplastic Lymphoma Kinase (ALK) acts on specific neurones in normal physiology and is also involved in the development of the brain. It is not known how ALK is physiologically activated, but it is thought that Heparin Binding Growth Factors act as the ligands to bind and activate ALK[2]. Nucleophosmin (NPM) is an RNA-binding nucleolar phosphoprotein. In normal physiology it is required to transport ribonucleoproteins between the nucleus and the cytoplasm of cells.

ALK+ALCLs tend to affect children and young adults and have a large male dominance. ALK+ALCLs also show a better prognosis when compared to ALK-ALCLs, with ALK+ having a 70-80% 5 year survival rate, whereas ALK- only has a 30-50% 5 year survival rate[3]. ALK-ALCLs generally show in the elderly population and are differentiated from ALK+ due to a raised serum LDL (Low Density Lipoprotein) level.

The t(2;5)(p23;q35) chromosomal transformation carried by the ALCL, leads to the activation of a full length ALK protein. This full length ALK protein is only found in tumour cells.

The jak/stat pathway

Regulation of the haemopoietic system is mainly by the action of small proteins called cytokines. Cytokines and their receptors are the main activators of the Jak-Stat pathway. Inactive Jaks bind to inactive cytokine receptors. When a cytokine binds to the receptor extracellular domain a conformational change is caused, which can rearrange dimmers or promote dimer/oligomer formation from monomeric chains[4]. The conformational change previously discussed is transmitted to the cytosolic juxtamembrane receptor domain which brings the catalytic and the active loops of Jak proteins[5] closer together, allowing Jaks to transphosphorylate and activate each other. These activated Jaks phosphorylate tyrosine residues on receptor cytosolic tails. The now phosphorylated receptor encourages the binding of SH2-containing proteins, the most important being the Stat proteins, which are situated in the cytoplasm in an inactive form[6]. After they are phosphorylated by Jak, the Stat proteins dimerize and translocate to the nucleus to act as a transcription factors for genes, which will affect the proliferation, growth and apoptosis of cells[6]. The Stats are also activated in response to growth promoting factors e.g. PDGF (Platelet Derived Growth Factor). In addition to this, Stats can also be activated by another mechanism involving the interaction of Stats with cytoplasmic tyrosine kinases e.g. Src and Abl.

Therefore the Jak-Stat pathway is vital in controlling cell fates in response to growth promoting factors and cytokines.

This pathway shows how vital the strict regulation of cytokines is, in the maintenance of stable cell activity. If cytokines, receptors and their binding partners are not present, the Jak proteins are kept as inactive complexes[7]. When cytokine-mediated receptor activation occurs and there is then Jak protein activation following this, there is a cascade of signalling which controls cell survival, proliferation and differentiation. In cancer there can be a mutation of the Jak protein (e.g. Jak2 mutation has been shown to form uterine leiomyosarcomas[8]), which when bound to membrane cytokine receptors and expressed in cells causes Jak to leave its inactive state and persistently activate the Stat proteins[9]. This activation of Stat leads to the oncogenic transformation and uncontrolled blood cell production shown in cancer.

All of the Stat proteins are common in certain features: 6 conserved domains, an oligomerization domain, a coiled-coil domain, a DNA binding domain, a linker domain, an SH2 domain (for receptor binding and dimerization) and a transcription activation domain. In cancer STAT3 and STAT5 activation is increased leading to increased expression of the genes involved in the cell cycle. Stat3 is the most commonly activated of the Stat family in patients with cancer (95% of head and neck cancers [10]). Of the Jak family of proteins, Jak3 is the major activator of Stat3. This fact is shown by ALK+ALCLs having highly activated Jak3 present[11]. Jak3 is also present in a form that is bound to NPM-ALK. The activation of Jak3 occurs in cytokines that possess the IL-2 common cytokine receptor y-chain. But IL-2 is not the only cytokine involved, Jak3 is also activated by IL-4, IL-7, IL-9, IL-15 and IL-21. When STAT3 activation occurs, there are a number of effects that contribute to tumorigenesis. STAT3 transforms fibroblasts to allow them to form tumours. It also suppresses p53 gene expression, which is located on the short arm of chromosome 17 and is involved in tumour suppression. The p53 gene works by preventing excessive cell proliferation and by preserving the integrity of DNA through DNA repair or apoptosis. This protein activation also promotes angiogenesis by increasing the expression of VEGF (Vascular Endothelial Growth Factor). Also there is an increased cell invasion due to the activation of a number of MMPs (Matrix Metalloproteinase). The activation of STAT3 can in addition to all of the previous effects cause the reduction is the production of pro-inflammatory cytokines and chemokines involved in the immune response, therefore making the growth and spread of cancer much easier.

Another method of the production of cancer is caused by NPM-ALK activating the PI3K/Akt pathway. PI3K (Phosphoinositide 3-Kinase) is activated due to receptor and non-receptor tyrosine kinase activation. This then phosphorylates PIP2 (Phosphatidylinositol-4,5-biphospate), which produces PIP3 (Phosphatidylinositol-3,4,5-triphosphate). PIP3 causes a number of substances to migrate to the plasma membrane including Akt (Protein Kinase B). At the plasma membrane another protein kinase which phosphorylates Akt. Levels of PIP3 are controlled by lipid phosphatases. This PI3K/Akt pathway regulates many cell processes, but in NPM-ALK lymphomas, activated Akt is over expressed and cell functions are disrupted, aiding tumorigenesis. Activated Akt does this by reducing the efficacy of the Bad protein, which is proapoptotic, and leads to its binding to cytoplasmic proteins. This process causes an increased release in Bcl-Xl (B-Cell Lymphoma Extra Large), which is a protein found in mitochondria and is involved in the survival of cancer cells. Activated Akt can also inhibit capase 9, this phosphorylates and therefore prevents the nuclear localization of the Forkhead box O (FoxO) family of transcription factors (FOXO1, FOXO3 and FOXO4). This in turn leads to an increase in tumorigenesis, due to the impaired cell function now caused. Normally Akt would promote cell survival by blocking the FOXO-induced expression of pro-apoptotic genes e.g. FasL and Bim.

The recognition of ALCLs was previously based entirely on the continued expression of CD30 in tumour cells. This is because it was seen as a TH2-specific marker, but more recent studies have shown that it is also present on t cells producing cytokines other than TH2 and it has also been found in TH1-dependant diseases[12]. CD30 is a membrane glycoprotein with 2 cytoplasmic domains to bind tumour necrosis factor receptor-associated factor (TRAF) proteins for signal transduction. The interaction of TRAF1, TRAF2 or TRAF5 with the binding sites of the cytoplasmic domain leads to the activation of NFkB transcription factor. NFkB controls the transcription of many cytokines including IL-2, IL-6, IL-8 and IL-12. The TRAF proteins can also control cell apoptosis, studies have suggested that the main activators are TRAF1 and TRAF2[13]. CD30 produces effects on adhesion molecule expression, chemokine production and chemokine receptor expression making CD30 vital in the spread of malignant cancer cells. There are 2 forms of the CD30 protein that can be seen. In one scenario there is a normal CD30 which induces cell apoptosis and protects the body against disease. But in neoplasms there is also NF-kB present which causes the lymphoma to proliferate. An over and continued expression of CD30 is related to the MAPK (Mitogen Activated Protein Kinase) signalling cascade. This continually raised expression of CD30 leads to the formation of cancer.

Ras is a small GTPase which is modulated by the MAPK cascade. In normal physiology Ras causes cell cycle arrest and stops the inappropriate cell proliferation found in cancer. Due to this fact the transformation that occurs in cancer must also cause inactivation of a tumour suppressor gene and the induction of telomerase (involved in cell replication). Ras activation is carried out by SOS (Sons of Sevenless) genes which encode guanine nucleotide exchange factors. SOS works by binding Ras-GTPases and making them release their bound nucleotide, which is often GDP. When released, the Ras-GTPase binds to a new guanine nucleotide which lies in the cytosol. As GTP is more common in the cytosol when compared to GTP, the Ras activation occurs. Ras is mediated by several SH2 and SH3 domain-containing adaptor proteins. NPM-ALK causes the activation of Ras and the phosphorylation of MAPK. Without Ras being present, NPM-ALK alone cannot cause cell transformation[14]. One of the factors important to cell tumorigenesis is the interaction of NPM-ALK with Grb2 (Growth factor Receptor-Bound protein 2), which is one of the adaptor proteins previously mentioned. The Ras mediated growth arrest is often accompanied by the induction of cyclin-dependant kinase inhibitors (CDKIs) and the down regulation of phosphorylated Rb (retinoblastoma gene)[15].

c-Myc is a gene which is associated with the expression of many genes involved in cell death and proliferation. The activation of the c-myc gene is carried out by STAMs (Signal-Transducing Adapter Molecules). These STAMs have conserved VHS and SH3 domains. STAM1 and STAM2A are phosphorylated by JAK1, JAK2 and JAK3, but the method by which this is done can be influenced by a third domain, the ITAM (Inducible Tyrosine-based Activation Motif). The full mechanism involved is not completely understood. But it is definitely known that the STAMs facilitate the transcriptional activation of specific target genes, mainly being the c-myc gene[16]. c-Myc gene activation is carried out by 2 methods depending on the type of cancer. In some ALCLs there are gene truncations within the 1st exon, 1st intron or flanking sequences. In other forms of cancer, there can be somatic point mutations or small re-arrangements within the regulatory regions of the c-myc gene spanning the 1st exon-1st intron boundary[17] . NPM-ALK tumours cause an increased expression of c-myc leading to a deregulation its target genes. c-Myc expression is shown in all ALK+ALCLs, but is never found in ALK-ALCLs[18].

Another molecule that plays an important role in the jak-stat pathway is IRF9. IRF9 fuses to the TAD of either STAT1 or STAT2 thereby activating these proteins so that they can carry out their function on DNA.

Negative feedback in the jak-stat pathway

With all of these genes controlling the continuation of the Jak-Stat pathway, there is clearly the need for a negative regulator of this process. This comes in the form of 3 methods: SH2 containing phosphatases (SHPs) which inactivate Jak proteins, Protein Inhibitor of Activated Stats (PIAS) which decreases the transcription of STAT3 and Suppressors of Cytokine Signalling (SOCS).

Src homology region 2 domain-containing phosphatase 1 (SHP-1) is a non-transmembrane protein tyrosine phosphatase all haemopoietic cells. Due to SHP-1 being a negative regulator of the jak-stat pathway and therefore protector against cancer, in ALK+ALCLs there is no SHP-1 expressed, it is effectively silenced and methylated in neoplasms. This loss of SHP-1 contributes to tumorigenesis because it does not check the activation and tyrosine phosphorylation of JAK3/STAT3[19]. Also the lack of SHP-1 leads to a reduced level of proteosome degradation of JAK3 and NPM-ALK.

There are 4 PIAS proteins that control Stat activity (PIAS-1, PIAS-3, PIAS-x and PIAS-y). Often in cancer there is an increase in PIAS-3 expression which will bind to activated STAT3 and prevent their binding to DNA. The expression of PIAS3 produces a protein which acts as an E3 SUMO protein ligase enzyme[20]. This SUMO (Small Ubiquitin-like Modifier) ligase enzyme catalyzes the covalent attachment of a SUMO protein to specific targets. When bound to transcription factors this protein can either block or enhance their activity. This "SUMOylation" is a post-translational modification that is required for the progression through the cell cycle.

SOCS are involved in the negative regulation of both cytokine and growth factor signalling. There is a collection of SOCS, from SOCS1-SOCS7. SOCS are stimulated by cytokines in a negative feedback loop and they also regulate signalling of other cytokines downstream by a process called 'cross-talk'[21]. The action of SOCS is based on the mechanism of SOCS1 and SOCS3. Both of these proteins block the Jak-Stat signalling pathway by inhibiting Jak kinase activity, aiding the degradation of Jak and Stat proteins and by competing with Stat for the binding sites on the cytokine receptors. As shown in the diagram below, CIS and SOCS2 compete with Stats for attachment to the receptor complex, thereby inhibiting the Jak-Stat signalling cascade.

The Stat phosphorylation that accompanies ALK+ALCLs is often joined by an increase in the expression of SOCS. This should be a beneficial effect (due to SOCS inhibiting the excessive Jak-Stat pathway activation), but even though this is occurring, it is thought that other mechanisms with negative effects on the Jak-Stat pathway may be blocked. Due to this overwhelming activation of the Jak-Stat cascade and only SOCS proteins present to inhibit this, the majority of the cancer cells can continue to proliferate and survive.

Current and future therapies for ALK+ALCLs

At the moment the treatment for ALK+ALCLs involves a combination chemotherapy containing doxorubicin. This gives a 95% remission rate, but a 40% chance of relapse in those patients[22]. The reason for this high relapse rate is not known, but it could be due to some tumour cells remaining dormant and only later expressing their effects on the patient. Also due to the large array of genes involved in the Jak-Stat pathway and the even greater variety of mutations that can occur, it is difficult to compare one patient to the next e.g. patients with a CD56 expressing tumour can have a better survival rate than those with high levels of c-Jun activation binding protein-1[23].

CD30 is a possible target for therapeutic agents as it plays a role in the development of cancer. In resting t and b cells only small amounts of CD30 is present, only when there is a neoplasm or the t cells are virus infected is the CD30 then released in greater amounts. The current treatment involves radiotherapy and excision, which is commonly an effective treatment, but there is the possibility of relapse. Due to the fact that CD30 is only expressed in these infected t cells, this provides a possible therapeutic target. From this, the clear possibility is immunotherapy. A possible treatment has shown that an immunotoxin made up of human angiogenin fused to a human CD30 ligand (Ang-CD30L) has a cytotoxic effect on CD30+ cells[24]. Another research has shown that there can be a viable treatment in the form of a chimeric monoclonal antibody aimed at CD30[25]. To this cAC10, they added a cytotoxic agent called monomethyl auristatin E (MMAE). When treating mice this showed to be a very effective and highly selective form of treatment for CD30+ lymphomas. One treatment that has been effective in clinical trials and is the closest to development involves the use of a bispecific protein molecule, with the ability to bind to both CD30 and CD64/FcyR1 (needed to trigger Fc-dependant killing in cells)[26]. As time goes on more selective and effective treatments will be produced, not only directed at CD30 but also the downstream targets.

The PI3/Akt pathway presents a possible therapeutic target as the inhibition of this pathway has been shown to remove the resistance that cancer cells may have against current therapies e.g. chemotherapy, hormone therapy etc[27]. If this technique could be used with conventional therapies, then there could be an increased rate in survival of cancer patients.

A potential way to reduce the proliferation seen in cancer cells is by using a compound called Cucurbitacin B. This drug works by inhibiting the activation of JAK2, STAT3, STAT5 and also by decreasing the expression of Bcl-XL and allowing the activation of the capase cascade[28]. Due to this large variety of effects all decreasing the proliferation ability of tumours, Cucurbitacin B could be used with other current chemotherapeutic agents to stop the spread of tumours and therefore reduce the risk of recurrence and increase survival rates.

Another anti-proliferation drug called triptolide, comes from a Chinese medicinal herb. Triptolide works by decreasing the release of IL6, JAK1 and phosphorylated STAT3. Due to the fact that this drug blocks major parts of the jak-stat pathway, it can be used as a treatment for neoplasms[29].

Another method of reducing lymphoma proliferation and inducing apoptosis is by targeting STAT5. This can be done with decoy oligodeoxynucleotides (ODN). This is done by transfection of the 21-mer-long STAT5 decoy ODN into specific cancerous cells[30]. Along with the decrease in proliferation and the induction of apoptosis the decoy ODN also caused down regulation of Bcl-XL and c-myc. This fairly new research shows the possibility of affecting the downstream targets of cancer and thereby stopping the whole process of cell proliferation by inhibiting the jak-stat pathway.

The negative regulation that occurs in the jak-stat pathway presents a clear method to inhibit the excessive cytokine signalling that is shown in cancer. In some forms of cancer there is a methylation-mediated silencing of SOCS3, if this is restored then there is the possibility that the cell proliferation can be stopped at an earlier stage. The re-activation of SOCS3 can be carried out via adenovirus mediated gene transfer[31]. Infection of cancer cells with this SOCS3-expressing vector stopped the growth of the neoplasm and induced apoptosis. Also the over-expression in this experiment showed that there is an increased radiosensitivity of the treated cells, therefore increasing the effectiveness of this treatment.

Due to many cancers involving a JAK2 mutation, a common treatment for these forms of cancer JAK2 kinase inhibitors can be used. But it has been clear that this treatment has limited efficacy in treating all neoplasms. In this research there is the potential for the use of a HSP90 inhibitor (PU-H71), which works by disrupting JAK2 protein stability[32]. This PU-H71 treatment caused a potent dose-dependent inhibition of both cell growth and the jak-stat pathway by degrading JAK2. The PU-H71 has also shown a reduction in the mutant allele burden in mice. All of these factors show the possible use of HSP90 inhibition in the treatment of JAK2 dependent neoplasms.

Due to the huge role of NPM-ALK in the tumour formation, this fusion gene clearly presents a possible therapeutic target. The first drug that was found to inhibit ALK was PF-02341066 which was initially made to block c-Met. This inhibitor causes the complete regression of NPM-ALK lymphomas. In cancer there are commonly point mutations in the kinase domain of the tyrosine kinases which impairs drug binding and is a major reason for acquired resistance to kinase inhibitors. As a result of this there is now a requirement for inhibitors with greater specificity against ALK.

Another method to specifically target the NPM-ALK gene has been carried out by indirectly inhibiting NPM-ALK e.g. inhibition of Hsp90 by Herbamycin A and 17-AAG[33]. But there can be a resistance to these treatments, thereby requiring combination therapy to treat ALK+ALCLs.

Immunotherapy shows as a possible treatment for ALK+ALCLs. As well as anti-CD30 antibodies, there is also the option of using CD26 as an immunotherapeutic target. Antibodies to CD26 play a role in mediating cellular functions. In this study, they show that binding a soluble anti-CD26 monoclonal Ab 1F7 inhibits the growth of CD30+ anaplastic large cell T-cell lymphoma[34]. IF7 has shown to cause cell cycle arrest at the G1-S checkpoint which reduces the proliferation of these cancerous cells. When the IF7 treatment was used on an immune-deficient mouse with tumour and this caused an inhibition of tumour formation.

Also gene therapy could be a future therapeutic method for ALK+ALCLs. One experiment has shown that the adenoviral-mediated transfer of p16, p21, p27 and p53 induces apoptosis and cell cycle arrest in these cancer cells[11]. Also there is another way of treating the ALK+ALCLs which is with the transfer of Shp1 which then supresses NPM-ALK, JAK3 and STAT3. In doing this the transfer of Shp1 effectively inhibits the jak-stat pathway and therefor the proliferation of neoplastic cells.

Due to the large role that STAT3 plays in the jak-stat pathway, this presents a therapeutic target. In this experiment, the ablation of STAT3 expression using antisense oligonucleotides (ASO) significantly (P<0.0001) impaired the growth of human and mouse NPM-ALK lymphomas[35].

Another experiment has shown that by using an adenovirus vector carrying a dominant-negative STAT3 (AdSTAT3DN) this can treat ALK+ALCLs. Infection by this AdSTAT3DN leads to expression of STAT3DN[36]. STAT3DN has a mutation on the 705 residue to convert tyrosine to phenylalanine, this portion is vital in the activation of STAT3 and nuclear translocation. The STAT3DN induces apoptosis and G1 cell cycle arrest. Also the STAT3DN causes capase-3 cleavage, downregulation of Bcl-XL, c-Myc and SOCS3.

JAK3 also shows as a target for therapeutic agents due to its involvement in the activation of STAT3. Treatment with a Jak inhibitor (AG490) reduces but unfortunately does not completely abrogate tyrosine phosphorylation of JAK3 and STAT3 in a concentration-dependent fashion[37]. This same result was shown with the use of some other Jak inhibitors, WHI-P131 and WHI-P154. All of these led to apoptosis with activation of capase 3 and a decreased expression of Bcl-Xl. Also there was a reduction in the S-phase of the cell cycle which could be due to downregulation of cyclin D3. The overall consequence was that there was a decreased activity of NPM-ALK with an increasing concentration of AG490.

NPM-ALK works by recruiting C-terminal SH2 domain of the phosphatidylinositol 3-kinase (PI3-Kinase). Therefore, there is the availability for the use of PI3-kinase inhibitors (Wortmannin and LY294002). When one of the PI3-kinase inhibitors was used it could cause apoptosis in NPM-ALK transformed cells[38]. This apoptosis led to overexpression of Bad (a pro-apoptotic molecule) which would be partially blocked by the overexpression of NPM-ALK. Of course in normal neoplasms NPM-ALK activates an anti-apoptotic PI3-kinase/Akt pathway leading to the generation of ALK+ALCLs.

In around 44% of ALK+ALCLs there can be an expression of the cyclin-dependant kinase (CDK) inhibitor p27Kip1 (p27)[39]. Activated Akt phosphorylates p27 and therefore increases p27 proteolysis and cell cycle progression. Through this experiment there is the ability to inhibit activated Akt activity in ALCLs which in turn decreases p27 phosphorylation and degradation, leading to an increase in the amount of p27 and the induction of cell cycle arrest. This process could be used to treat ALK+ALCLs and decrease their spread in human cells.

JAK3 activation only occurs in relation to interleukins that recruit the common y-chain (yc) receptor e.g. IL-9. IL-9 has been shown to play a role in the formation of ALK+ALCLs due to its activation of JAK3. Due to the role of IL-9 it has formed the basis of a treatment in the form of an anti-IL-9-neutalizing antibody which decreased phosphorylated JAK3, phosphorylated STAT3 and ALK kinase activity[40]. This therefore induced cell cycle arrest and a decrease of the proliferation these neoplastic cells. The cell cycle arrest is due to the up-regulation of p21 and down-regulation of Pim-1.

Many ALK+ALCLs do not include the expression of SHP1 which is a negative regulator in the jak-stat pathway. In cell lines the inhibition of SHP1 expression causes an increase in phosphorylated JAK3, phosphorylated STAT3 and NPM-ALK[19]. Therefore in the opposite scenario where SHP1 is expressed, there is a decrease in all of these proteins. SHP1 expression was shown to lead to G1 cell cycle arrest, but there was no apoptosis present.


From this research it is clear that cell signalling in ALK+ALCLs in vital in the progression of the disease. One of the major cell signalling pathways involved in this process is the jak-stat pathway. This pathway is extremely complicated but each path of the cascade contributes to the pathogenesis of the neoplasm. But with all of these pathways comes a benefit in the form of therapeutic agents. Due to the many signalling molecules involved, there is a much wider range of targets for therapeutic agents. This great variety of therapeutic targets gives the possibility for lots of research to take place in this area. Some of the most effective treatments discussed in this article include immunotherapy that can be specific to certain signalling molecules. With further research a treatment with a greater efficacy could be produced, I believe this can be done by not only targeting one signalling molecule, but instead by targeting a number of molecules and stopping the signalling cascade and therefore the progression of oncogenesis. With time and continued research into this field of cancer treatment there will be results in treating not only ALK+ALCLs but this can also improve our knowledge in other forms of cancer and hopefully someday, increase survival rates in all cancers.