• Biomolecules & Therapeutics
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• v.29 no.5
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• pp.551-561
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• 2021

Thyroid cancer is the most common endocrine malignancy. Patients with well-differentiated thyroid cancers, such as papillary and follicular cancers, have a favorable prognosis. However, poorly differentiated thyroid cancers, such as medullary, squamous and anaplastic advanced thyroid cancers, are very aggressive and insensitive to radioiodine treatment. Thus, novel therapies that attenuate metastasis are urgently needed. We found that both PDGFC and PDGFRA are predominantly expressed in thyroid cancers and that the survival rate is significantly lower in patients with high PDGFRA expression. This finding indicates the important role of PDGF/PDGFR signaling in thyroid cancer development. Next, we established a SW579 squamous thyroid cancer cell line with 95.6% PDGFRA gene insertion and deletions (indels) through CRISPR/Cas9. Protein and invasion analysis showed a dramatic loss in EMT marker expression and metastatic ability. Furthermore, xenograft tumors derived from PDGFRA geneedited SW579 cells exhibited a minor decrease in tumor growth. However, distant lung metastasis was completely abolished upon PDGFRA gene editing, implying that PDGFRA could be an effective target to inhibit distant metastasis in advanced thyroid cancers. To translate this finding to the clinic, we used the most relevant multikinase inhibitor, imatinib, to inhibit PDGFRA signaling. The results showed that imatinib significantly suppressed cell growth, induced cell cycle arrest and cell death in SW579 cells. Our developed noninvasive apoptosis detection sensor (NIADS) indicated that imatinib induced cell apoptosis through caspase-3 activation. In conclusion, we believe that developing a specific and selective targeted therapy for PDGFRA would effectively suppress PDGFRA-mediated cancer aggressiveness in advanced thyroid cancers.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.17
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• pp.7415-7423
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• 2015

Chronic myeloid leukemia (CML) is a stem cell disorder characterized by unrestricted proliferation of the myeloid series that occurs due to the BCR-ABL fusion oncogene as a result of reciprocal translocation t(9;22) (q34;q11). This discovery has made this particular domain a target for future efforts to cure CML. Imatinib revolutionized the treatment options for CML and gave encouraging results both in case of safety as well as tolerability profile as compared to agents such as hydroxyurea or busulfan given before Imatinib. However, about 2-4% of patients show resistance and mutations have been found to be one of the reasons for its development. European Leukemianet gives recommendations for BCR-ABL mutational analysis along with other tyrosine kinase inhibitors (TKIs) that should be administered according to the mutations harbored in a patient. The following overview gives recommendations for monitoring patients on the basis of their mutational status.

• Clinical and Experimental Pediatrics
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• v.54 no.3
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• pp.106-110
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• 2011

In pediatric patients with acute lymphoblastic leukemia (ALL), the Philadelphia chromosome translocation is uncommon, with a frequency of less than 5%. However, it is classified as a high or very high risk, and only 20-30% of Philadelphia chromosome-positive (Ph+) children with ALL are cured with chemotherapy alone. Allogeneic hematopoietic stem cell transplantation from a closely matched donor cures 60% of patients in first complete remission. Recent data suggest that chemotherapy plus tyrosine kinase inhibitors (TKIs) may be the initial treatment of choice for Ph+ ALL in children. However, longer observation is required to determine whether long-term outcome with intensive imatinib and chemotherapy is indeed equivalent to that with allogeneic related or alternative donor hematopoietic stem cell transplantation (HSCT). Reports on the use of second-generation TKIs in children with Ph+ ALL are limited. A few case reports have indicated the feasibility and clinical benefit of using dasatinib as salvage therapy enabling HSCT. However, more extensive data from clinical trials are needed to determine whether the administration of second-generation TKIs in children is comparable to that in adults. Because Ph+ ALL is rare in children, the question of whether HSCT could be a dispensable part of their therapy may not be answered for some time. An international multicenter study is needed to answer the question of whether imatinib plus chemotherapy could replace sibling allogeneic HSCT in children with Ph+ ALL.

• Journal of Veterinary Clinics
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• v.34 no.2
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• pp.94-97
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• 2017

A 10-year-old male Schnauzer dog presented with a 1-week history of ataxia, right-sided hemiparesis, and right-sided head tilt. On the basis of magnetic resonance imaging (MRI) with neurological examination and cerebrospinal fluid analysis results, a primary brain tumor was suspected. Therapy with imatinib mesylate plus hydroxyurea for 7 weeks was not effective and clinical signs worsened. Chemotherapy was then changed to lomustine plus hydroxyurea. Although the existing clinical signs continued, they did not deteriorate. No change in mass size was observed in subsequent MRI. The subject suddenly died from dyspnea 388 days after initial presentation. In this case, choroid plexus papilloma was definitively diagnosed based on histopathological findings.

• Korean journal of aerospace and environmental medicine
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• v.31 no.3
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• pp.82-83
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• 2021

Chronic myeloid leukemia (CML) is myeloproliferative neoplasm associated with a characteristic chromosomal translocation (bcr-abl) called Philadelphia chromosome which plays a key role in the pathogenesis. Approximately 85% of patients with CML are in the chronic phase at the time of diagnosis. During this phase, patients are well tolerated and have few symptoms. But untreated, over the course of several years progresses to an accelerated phase and ultimately to a blast crisis, the terminal phase. CML is largely treated with targeted drug therapy called tyrosine-kinase inhibitors (TKIs) which have led to dramatically improved long-term survival rates since 2001. These drugs became standard treatment of this disease and allow most patients to have much better quality of life when compared to the former chemotherapy drugs and the bone marrow transplantation. Imatinib (Gleevec or Glivec, Norvatis) was the first of these TKIs and found to inhibit the progression of CML in the majority of patients (65%-75%) sufficiently to achieve remission. Since the advent of imatinib, CML has become the first neoplasm in which a medical treatment can give to the patient a normal life expectancy.

• Biomolecules & Therapeutics
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• v.32 no.5
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• pp.582-600
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• 2024

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment landscape for chronic myeloid leukemia (CML). However, TKI resistance poses a significant challenge, leading to treatment failure and disease progression. Resistance mechanisms include both BCR::ABL1-dependent and BCR::ABL1-independent pathways. The mechanisms underlying BCR::ABL1 independence remain incompletely understood, with CML cells potentially activating alternative signaling pathways, including the AKT/mTOR and JAK2/STAT5 pathways, to compensate for the loss of BCR::ABL1 kinase activity. This study explored tumoral VISTA (encoded by VSIR) as a contributing factor to TKI resistance in CML patients and identified elevated tumoral VISTA levels as a marker of resistance and poor survival. Through in vitro and in vivo analyses, we demonstrated that VSIR knockdown and the application of NSC-622608, a novel VISTA inhibitor, significantly impeded CML cell proliferation and induced apoptosis by attenuating the AKT/mTOR and JAK2/STAT5 pathways, which are crucial for CML cell survival independent of BCR::ABL1 kinase activity. Moreover, VSIR overexpression promoted TKI resistance in CML cells. Importantly, the synergistic effect of NSC-622608 with TKIs offers a potent therapeutic avenue against both imatinib-sensitive and imatinib-resistant CML cells, including those harboring the challenging T315I mutation. Our findings highlight the role of tumoral VISTA in mediating TKI resistance in CML, suggesting that inhibition of VISTA, particularly in combination with TKIs, is an innovative approach to enhancing treatment outcomes in CML patients, irrespective of BCR::ABL1 mutation status. This study not only identified a new pathway contributing to TKI resistance but also revealed the possibility of targeting tumoral VISTA as a means of overcoming this significant clinical challenge.

• Biomolecules & Therapeutics
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• v.23 no.2
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• pp.99-109
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• 2015

Drug development groups are close to discovering another pot of gold-a therapeutic target-similar to the success of imatinib (Gleevec) in the field of cancer biology. Modern molecular biology has improved cancer therapy through the identification of more pharmaceutically viable targets, and yet major problems and risks associated with late-phase cancer therapy remain. Presently, a growing number of reports have initiated a discussion about the benefits of metabolic regulation in cancers. The Warburg effect, a great discovery approximately 70 years ago, addresses the "universality" of cancer characteristics. For instance, most cancer cells prefer aerobic glycolysis instead of mitochondrial respiration. Recently, cancer metabolism has been explained not only by metabolites but also through modern molecular and chemical biological techniques. Scientists are seeking context-dependent universality among cancer types according to metabolic and enzymatic pathway signatures. This review presents current cancer metabolism studies and discusses future directions in cancer therapy targeting bio-energetics, bio-anabolism, and autophagy, emphasizing the important contribution of cancer metabolism in cancer therapy.

• Clinical and Experimental Pediatrics
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• v.52 no.6
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• pp.643-648
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• 2009

Blood eosinophilia can be classified as either familial or acquired. Familial eosinophilia is a rare autosomal dominant disorder characterized by a stable eosinophil count. Acquired eosinophilia is classified further into a primary or secondary phenomenon depending on whether eosinophils are considered integral to the underlying disease. Primary eosinophilia is considered clonal in the presence of either a cytogenetic abnormality or bone marrow histological evidence of classified hematologic malignancies. Causes of secondary eosinophilia include infections, allergic or immunologic disorders, and drugs. Idiopathic eosinophilia belongs to a category of primary eosinophilia, and this is a diagnosis of exclusion. Cases with eosinophilia that lack evidence of clonality may be diagnosed as idiopathic hypereosinophilic syndrome after all causes of reactive eosinophilia have been eliminated. Genetic mutations involving the platelet-derived growth receptor genes (PDGFRA and PDGFRB) have been pathogenetically linked to clonal eosinophilia, and their presence predicts the treatment response to imatinib. In this review, I will present a clinical summary of both familial and acquired eosinophilia with emphasis on recent developments in molecular pathogenesis and treatment.

• Proceedings of the Korean Society for Bioinformatics Conference
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• 2004.11a
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• pp.203-209
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• 2004

Molecular docking using Lamarckian genetic algorithm of AutoDock 3.0 (AD3) was employed to understand in retrospect the selectivity of phenylaminopyrimidine (PAP) derivatives against the kinase domain c-Abl, implicated in chronic myelogenous leukemia (CML). The energetics of protein-ligand complex was scored using AD3 to identify active drug conformations while Ligplot and ligand protein contact (LPC) programs were used to probe schematic molecular recognition of the bound inhibitor to the protein. Results signify correlation between model and crystal structures of STI-571 compound or Imatinib (IM), a PAP derivative and now clinically proven for its efficacy in CML. A prospect active form Abl inhibitor scaffold from matlystatin class of compounds will be published elsewhere.

• Applied Microscopy
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• v.47 no.4
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• pp.233-237
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• 2017

Chronic eosinophilic leukemia (CEL) is a myeloproliferative disease with an increased number of mature eosinophils and their precursors, which results in infiltration into organs and organ enlargement. The main cause of this disease is the overexpression of tyrosine kinase. However, there is a need for alternative medication, because some patients are resistant to imatinib, which is a tyrosine kinase inhibitor for leukemia. Many studies have indicated that S100A8 and splicing factor proline and glutamine-rich (SFPQ) function as initiation signals of apoptosis in CEL cells. We reviewed structural studies on CEL cells related to S100A8 and SFPQ. Particularly, this review highlighted microscopic results for the study of S100A8 and SFPQ in CEL cells.