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Chronic myeloid leukemia which is also known as chronic myelogenous leukemia, is a slow growing cancer of blood forming tissue. A genetic change leads to abnormal behaviour of blood producing myeloid cells, turning out uncontrolled growth of these cells. The primary reason is translocation of t(9,22), where parts of ABL1 gene from chromosome 9 fuses with BCR gene from chromosome 22, leading to form abnormal fusion gene named as BCR-ABL1. Depending upon the stages of disease, different therapies are chosen to treat the patient. Currently most used and successful therapies is Targeted tumour suppressor therapies which are inhibitors of tyrosine kinase, where drugs are targeted against BCL-ABL1 Tyrosine kinase, leading to downregulation and blockage of transformed leukemia cells. However, every treatment comes with its limitation. Even though TKI targeted therapy has increase life expectancy of CML patients, there is notable resistance against these drugs with gradual time increase. Thus, limitation with primary and secondary treatments using these drugs has opened doors to more advanced research to overcome this. In my opinion, current targeted therapy for CML is effective but this needs improvement in regard to increase efficacy, to overcome resistance and to lower down adverse drug effects. The development of more proof-reading technology is needed to cure this condition and for this to effect, more in depth molecular probes are needed in area of CML and followed by one or more therapies may be combined to control the progression of disease, thus increasing life expectancy of CML patients.
Keywords: Tumour suppressor, TKI (Tyrosine kinase inhibitors), BCL-ABR1, chronic myeloid leukemia, Imatinib, AlloSCT, Apoptosis
The current opinion paper is based on one of the cancer forms which arise from bone marrow and its targeted therapies along with its advantage and drawbacks, mentioning the future prospective to inhibit progression of disease. Chronic myeloid leukemia (CML) is one of the life-threatening cancers of bone marrow, which is blood forming tissue. This starts with stem cells present in blood, giving rise to uncontrolled growth of blast cells leading to over production of abnormal cells. The central reason of this pathogenesis is the fusion of Abelson murine leukemia (ABL1) gene on chromosome 9 with cluster region (BCR) gene on chromosome 22. This fusion leads to express oncoprotein called as BCR-ABL1. This is constitutively activated tyrosine kinase, leading to promotion of growth and activation of downstream pathways involving RAS, MYC, STAT. This results in cytokine independent cell cycle with interfered apoptotic signals in response to cytokine withdrawals (Konopleva 2017). The mechanism has been introduced in
Figure 1: Mechanism of CML
Translocation between Chromosome 9 and 22, creating abnormal BCR-ABL Source: McMaster University
The examination or blood test help to define stages within CML. Majorly three phases have been classified as: Chronic phase CP, Accelerated phase (AP) and Blast Phase (BP). Chronic phase cells are responsive to many growth factors, leading to reduced apoptosis, abnormal adhesion and activation of downstream pathways. CML then turns eventually into AP followed by BP where molecular changes in downstream pathways lead to increase in abnormalities in p53, Rbl gene mutation etc (Bacco 2000). Progression from chronic to blast phase is characterized by an increase in genetic instability, accumulating genetic and cytogenic abruptions. The conventional treatments were used initially to treat this disease which included spleen irradiation, allogeneic stem cells transplantation, interferon-Alpha or hydroxycarbamide. However, none of this had been succeeded in regression. Allogeneic transplantation was dependent on donors which led to limited offerings. IFN-a led to disease regression in some of the patients but it was hindered by its efficacy and toxicities associated with treatment. The introduction of Tyrosine kinase inhibitors (TKIs) as tumour suppressor therapy has revolutionised the treatment of CML. The TKIs interferes the interaction between BCR-ABL1 oncoprotein and adenosine triphosphate (ATP), blocking their cellular proliferation of leukemoid stem cells. This targeted therapy has improved survival rate of patients from 20 to 80 % (Jabbour 2018).
SOURCES OF STRATEGY
To search out pathogenesis and molecular pathways of Chronic myeloid leukemia, I started to look out the basic information using web browser as google. After understanding the molecular pathways for CML, I searched out and brainstormed therapies available to treat the disease with their efficacies and implications. With extensive research and browsing using www.Google.com and online tools of Leddy Library, University of Windsor (http://leddy.uwindsor.ca/biology ), I collected authentic research literatures including research papers and review articles.
The papers allowed me to explore pathways associated with CML disease and its experimental models to develop different regressive therapies. Also, with current trends with targeted therapies, they do have major set backs as well. The new future direction will be driven with this as a base and new therapies will be developed to target the disease with more efficacy, eliminating major drawbacks and limitations. The figures are mentioned as below as Figure 2.
Figure 2: Search strategy for CML and its therapy
Collection of literature to make thesis statement Source: Leddy Library/Google/Web browser/Search engine
Chronic myeloid leukemia is a very rare disease, with limited cases worldwide. However due to various oncogenic factors, there has been increasing number of patients worldwide as compare to before (Jabbour 2018). Currently used therapy to treat the disease condition is based on Tyrosine kinase inhibitors which interfere within ATP and BCR-ABL1 protein interaction.
As BCL-ABR1 tyrosine kinase plays central role in CML, most used strategy is development of Tyrosine kinase inhibitors. Non-mutated ABL1 plays important role in regulation of cell motility, adhesion, autophagy and proliferation of cells. However, in CML, mutant fusion protein leads to constitutive expression of ABL1 kinases, leading to uncontrolled proliferation of cells (Charles 2004). The current tyrosine kinase inhibitors work with either ATP competitive inhibitors or allosteric inhibitors as. One such potent drug created to work as ATP competitive inhibitors is Imatinib mesylate (Brand name: Gleevec), is approved for first line therapy (Iqbal 2014). It binds closer to ATP binding site, locking it in a closed conformation, thus terminating the enzyme activity, followed by switching off the downstream signalling cascade which promote leukemogenesis as mentioned in Figure 3.
Figure 3: Imatinib: Mode of action
Imatinib blocks the ATP binding site thus downregulating abnormal pathways, leading to elimination of cancer cells
Source: Mauro et al 2001
Dasatinib is second line treatment drug which not only inhibits ABL1 but also inhibits altered molecules such as c-KIT, SRC kinase, PDGFRβ which are involved in CML with downstream pathways. In this way it is more potent than Imatinib. Nilotinib is also a derivative related to Imatinib, which is highly potent and more specific to BCR-ABL1. These second line treatments are more potent than first line but they do not show any significant difference to survival rate of disease. Bosutinib is one of the allosteric inhibitors which blocks the SH3-SH2 binding site, thus inactivating kinase and downstream pathways (Soverini 2018). The current therapy shows significant improvement in progression of disease. Imatinib and other second line treatments show almost 80% survival rate by inducing complete haematological response and complete cytogenetic response. The second line and front-line treatments show higher response even at molecular level inhibiting many oncogenes or altered genes which promotes growth of cancel cells. They are more effective and induce deeper molecular response as compare to imatinib (Ciarcia 2016). They are more beneficial to patients with high risk disease, where they reduce rate of transformation from CP to BP, leading to increase survival. This treatment are long lasting with excellent outcome. And also this is cost effective as compare to other substitutive treatments such as Allo stem cell therapy (Jabbour 2018).
However, TKI targeted therapy has shown a limitation with drug resistance. Patients with first line treatment suddenly stop responding to treatment due to resistance. Point mutation within BCL-ABL kinase domain leads to resistance to TKIs therapy. Around 30% patients stop responding to Imatinib due to such resistance (Chen et al 2011). Majorly T315I is most common mutation and also it inactivates second line generation treatment as well. The blockage is mainly due to conformation change which leads to steric hindrance, blocking imatinib binding site or due to increase in amplification or mRNA level of BCR-ABL gene. Such mutations lead to gain of function alterations, thus encouraging the downstream pathway and ultimately proliferation of leukemic cells. Off target effects are pointing towards substitution which may help to prevent progression of CML as stand by or in combination.
With increasing resistance against TKIs, AlloSCT which is identified previously has been become escape gate to eradicate the disease progression. Even though it has limitation over donors and high costing, AlloSCT along with selectable TKIs show prominent result, indicating a salvage therapy for minority patients with high risk or advanced stage of CML (Eskazan 2018). Also research is becoming advanced with non-ATP site allosteric inhibitors or adding ABL kinase inhibitors which are at early clinical development, namely PF114 (Fusion Pharma) and K0706 (Sun Pharma advanced research company), giving promising treatments to overcome current limitations and expanding TKI horizons.
Most CML patients would have normal life span and can be potentially function, however they will not be expected to be cured from molecular response from CML as long as they continue with TKI treatments. Also, resistance to drugs must be observed in timely manner to avoid serious implications with this therapy. This can be overcome with highly potent new generation TKIs or in combination with other available or investigational therapies which may improve eradication of disease and need of indefinite TKIs therapies to cure the disease condition. In conclusion, the current Targeted therapy in CML is effective enough to fight early stages of CML but stronger and effective therapies are going to be still in huge demand to responds to small group of patients with advanced stage of CML or to overcome resistance of current therapies. Also TKIs are unable to completely eradicate the cells. So new research is being directed towards understanding critical pathways for leukemic stem cells, differing them from normal stem cells pool and targeting these LSCs, to completely cure CML. In my opinion, targeted approach is entering to new era to giving hope not only to CML but in widen area of treatments to cure or terminate progress of advanced stages of various types of cancer.
I would like to extent my gratitude to Dr. Tranum Kaur for giving us opportunity to write such in depth scientific article based on our thesis statement. I would also like to thank University of Windsor, Leddy Library for proving us access to such a vast collections of research articles.
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