A System Biology Perspective to Overcoming the Challenges of JAK Inhibition Mon Therapy for Myeloproliferative Neoplasms: An Overview

Alphonsus Ogbonna Ogbuabor^1*, Peter Uwadiegwu Achukwu², Silas Anayo Ufelle^1,2 and Daniel Chukwuemeka Ogbuabor^1,3
*Correspondence: Dr. Alphonsus Ogbonna Ogbuabor, Department of Hematology, Enugu State University of Science and Technology Teaching Hospital, Parklane, Enugu, Enugu State, Nigeria, Email:

Keywords

JAK-STAT pathway • JAK inhibitors • Therapy • Myeloproliferative neoplasm • System biology

About the Study

System biology provides a good analytical tool to understand, predict, and control of biological processes particularly for blood cell production as well as hematological malignancies such as myeloproliferative neoplasms [1,2]. Myeloproliferative neoplasms are heterogeneous hematopoietic stem cell disorders that involve mutations which activate the physiological signal-transduction pathways associated with activated JAK- STAT signaling [3,4]. The current World Health Organization classification of Myeloproliferative neoplasms have identified Chronic Myeloid Leukaemia, Chronic Neutrophilic Leukaemia, Polycythemia Vera, Primary Myelofibrosis, Essential Thrombocythemia, Chronic Eosinophilic Leukaemia and other unclassified neoplasms [5]. They are classified into three groups of (i) Neoplasms with Philadelphia positive chromosome such as Chronic Myeloid Leukaemia (ii) Neoplasms with Philadelphia negative chromosome such as Polycythemia Vera, Essential Thrombocytopenia, Primary Myelofibrosis and (iii) other uncommon myeloid neoplasms including Chronic Eosinophilic Leukaemia, Chronic Myelomonocytic Leukaemia and Systemic Mastocytosis [6]. Studies identified three main mechanisms of pathophysiology which include (iv) somatic driver mutations that stimulate activation of JAK STAT pathway (v) cooperating driver mutations in myeloid genes and (vi) uncommon genetic factors that initiate different clinical neoplastic phenotypes.

The Role of JAK-STAT Pathway

In 2005, the activating V617F mutation in the exon 14 of the JAK 2 gene (JAK2V617F) was identified in 50% of myeloproliferative neoplasm patients. Following this, other JAK 2 mutations such as mutation in the exon 9 gene encoding for calreticulum (CALR) were identified in 25% of cases and in a minority of about 5% a mutation in MPL exon 10 was identified [7,8]. The discovery in myeloproliferative neoplasm patients of mutations affecting JAK 2 signaling led to the identification of deregulated signaling through the JAK-STAT pathway as a major pathogenic mechanism of clonal proliferation and the development of drugs targeting JAK 2 [9]. Ruxolitinib was the first JAK 2 inhibitor approved for therapy of myeloproliferative neoplasms [10]. Several other JAK 2 inhibitors have been developed for patients with myeloproliferative neoplasms but have been discontinued due to toxicity.

JAK inhibition therapy

Following the identification of activating mutations in the JAKSTAT pathway, there was considerable effort put into the development of substances that can target the kinase activity of JAK 2. These are commonly referred to as the JAK inhibitors. JAK inhibitors could be classified into two groups of allosteric and non-allosteric inhibitors depending on their mechanism of action and region targeted for therapy.

Non-allosteric inhibitors

There are two types namely the type 1 inhibitors and type II inhibitors. While type I inhibitors target the ATP-binding site of JAK2 in the active conformation of the kinase domain, the type II inhibitors target the ATP-binding site of its kinase domain in the inactive conformation. Type I inhibitors have been prominent in the management of myeloproliferative disorders. Ruxolitinib, a Type I inhibitor has been recently approved for the treatment of myeloproliferative disorders by the US food and Drug Administration. Though at the early stages of clinical trials, type II inhibitors are more effective and powerful than type I inhibitors. Two type II inhibitors (NVP BBT594 and NVP-CH2868) have been developed. The NVP – BBT594 was effective in myeloproliferative neoplasm cellular models while NVP-CH2868 has been effective in preclinical mouse myeloproliferative models [11,12].

Allosteric inhibitors

These are inhibitors which bind to other sites different from the ATP-kinase binding active sites. There are two types namely type III inhibitors which bind to a site close to the ATP-binding site (e.g. LS104) and type IV inhibitors which bind to an allosteric site far from the ATP-binding Site (e.g. ONO44580). Targeting regions outside the ATP-binding site provides an advantage of higher selectivity and the possibility to overcome drug resistance by targeting two different sites in a combinatorial therapy model [13,14]. There are currently no JAK allosteric inhibitor in clinical use.

The Challenges of JAK Inhibition Therapy

p> The aim of JAK 2 inhibition therapy for myeloproliferative neoplasms has not been achieved. There are limitations with respect to limited efficacy, selectivity and doselimited toxicities [15]. There is need for new inhibitors or combination therapies which will not only ameliorate symptoms but could arrest clonal proliferation of the myeloid stem cells. New generation of JAK 2 inhibitors such as allosteric inhibitors targeting unique sequences in JAK 2 are needed to be developed. Such inhibitors will be less toxic and will target the clonal complexities of the disease [16].

Perspective for a System Biology Framework

System biology provides a network analysis of disease related genes and drug targeting of signaling pathways which could enable the discovery of drugs with the potential desired effects for a given disease [17,18]. Proteomics enables integrated view of biological systems by studying all the transduced proteins in a cell [19]. This can be applied to enhance our understanding of the complexity of multiple molecular mechanisms implicated myeloproliferative neoplasms with respect to JAK inhibitor interactions. Integrated proteomics technologies are currently being explored for various cancer phenotypes to identify common mechanisms that drive the clonal proliferation of cells including aberrant metabolomics [20].

Conclusion

JAK inhibition remains a novel therapeutic target for myeloproliferative neoplasms. System biology presents a dynamic tool that could be strategically applied in JAK inhibition for designing dose regimens, drug repurposing and combination therapies for future interventions on patients with myeloproliferative neoplasms.

References

1. Lorand,Gabriel Parajdi, Radu Precup, Eduard Alexandru Bonci and Cyprian Tomuleasa. “A Mathematical Model of the Transition from Normal Hematopoiesis to the Chronic and Accelerated Acute Stages in Myeloid Leukemia,” Mathematics 8 (2020) :1-18
2. Jerry, Spivak. “Myeloproliferative Neoplasms”. N Engl J Med 376 (2017): 2168-2181.
3. David, Williams. “Pairing JAK with MEK for Improved Therapeutic Efficiency in Myeloproliferative Disorders.” J Clin Invest 129 (2019): 1519-1521.
4. Qiong, Yang, John Crispino and Qiang Jeremy Wen. “Kinase Signaling and Targeted Therapy for Myelofbrosis.” Experimental Hematol 48 (2017): 32-38.
5. Mi-Ae, Jang and Chul Won Choi. “Recent Insights Regarding the Molecular basis of Myeloproliferative Neoplasm.” Korean J Intern Med 35 (2020)1:1-11.
6. Yudith, Annisa Ayu Rezkitha, Ugroseno Yudho Bintoro and Ami Ashariati. “The Role of JAK 2 in Myeloproliferative Disease Diagnosis.” Biomolecular Health Sci J 1(2018) :135-140.
7. Morten, Andersen, Zamra Sajid, Rasmus Pedersen and Johanne Gudmand-Hoeyer, et al. “Mathematical Modeling as a Proof of Concept for MPNs as a Human Inflammation Model for Cancer Development.”PLOS ONE 12 (2017) :e0183620.
8. Palumbo, Giuseppe, Stefania Stella, Maria Stella Pennisi and Cristina Pirosa, et al. “The role of New Technologies in Myeloproliferative Neoplasms.” Frontiers Oncol 321(2019) :1-10.
9. Elena, Maria Elli, Claudia Barate, Francesco Mendicino and Francesca Palandri, et al. “Mechanisms Underlying the Anti-inflammatory and Immunosuppressive Activity of Ruxolitinib.” Frontiers Oncol 118 (2019):1-10.
10. Alessandro, Vannuchi and Claire Harrison. “Emerging Treatment for Classical Myeloproliferative Neoplasm.” Blood 130 (2017) :693-703.
11. Bing, Li, Raajit Rampal and Zhijian Xiao. “Targeted Therapies for Myeloproliferative Neoplasms.” Biommarker Res 7(2019):1-8.
12. Elf, Mullally. “Targeting Specific mutations in Myeloproliferative Neoplasms”. Eur Hematol Association 11 (2017):157.
13. Nahla, Hamed. “JAK2 and its Regulators beyond Myeloproliferative Neoplasms.” J Tumor Med Prev 2 (2018):555598.
14. Leroy,Constantinescu. “Rethinking JAK 2 Inhibition: Towards Novel Strategies of more Specific and Versatile Janus Kinase Inhibition.” Leukemia I (2017):16
15. Shank, Kaitlyn, Andrew Dunbar, Priya Koppikar and Maria Kleppe, et al. “Mathematical Modeling Reveals Alternative JAK Inhibitor Treatment in Tyeloproliferative neoplasms.”Haematologica 105 (2020):e93.
16. Azam, Peyvandipour, Nafiseh Saberian, Adib Shafi and Michele Donato, et al. “A Novel Computational Approach for Drug Repurposing Using System Biology.”Bioinformatics 34 (2018) :2817-2825.
17.  Alphonsus, Ogbonna Ogbuabor, Achukwu Peter Uwadiegwu, Ufelle Silas Anayo , Daniel Chukwuemeka Ogbuabor, et al. “The Cytokine Network: An Integrated Approach to Understanding the Mechanism of Unexplained Recurrent Implantation Failures.” J Cytokine Biol 4 (2019):130.
18. Amit,Kumar Banerjee. “Computation in Analyzing Inflammation: A General Perspective.” Interdiscip J Microinflammation 3 (2015) :1-4.
19. Aikaterini, Koutsi and Elisavet-Christina Vervesou. “Diagnostic Molecular Techniques in Hematology: Recent Advances.” Ann Transl Med 6 (2018) :242.
20. Cassie, Clarke and Holyoake Tessa. “Preclinical Approaches in Chronic Myeloid Leukemia: from Cells to Systems.”Experimental Hematol 47(2017):13-23.