Imatinib, which was the first targeted therapy for patients with chronic myeloid leukemia (CML), has led to the significant prolongation of life for most patients. However, approximately 30% fail therapy. The major mechanism of acquired resistance is somatic mutation within the BCR-ABL1 kinase domain, which affects imatinib binding. Recently, more potent inhibitors have been approved that retain activity against most of the more than 100 mutations. However, some mutations remain problematic for one or more of the new inhibitors. The most frequently detected mutation, T315I, remains resistant to all of the currently approved inhibitors. More sensitive mutation techniques that focus on the detection of a limited number of specific mutations may be beneficial, but are yet to prove their clinical utility for the early detection of relapse in routine practice.
Inhibitors with alternate binding modes that may overcome T315I-associated resistance are at the preclinical stage or are undergoing clinical trial.
Each of the new, more potent kinase inhibitor drugs appear to have a partially overlapping set of mutations that confer a degree of resistance. Mutation detection techniques may need to adapt to provide clinicians with a more timely indication of mutation acquisition and pending relapse.
"ongoing controversies with regard to the simple use of tables listing mutations and 50% inhibitory concentration (IC 50 ) values. Some experts believe that the latter on its own should not guide physician choices for therapy (Khorashad et al, 2006; Redaelli et al, 2009; Laneuville et al, 2010; Branford & Hughes, 2011). Data from in vitro analyses do not account for factors relevant in vivo, such as protein binding and activity of cellular influx/efflux pumps or a variety of other factors affecting clinical response to a 2G TKI, and thus generally provide an inadequate predictability of treatment response (Bixby & Talpaz, 2011). "
[Show abstract][Hide abstract] ABSTRACT: Chronic myeloid leukaemia in children and young people is a relatively rare form of leukaemia that shows increased incidence with age and some evidence suggests that the molecular basis differs from that in adults. Significant advances in targeted therapy with the development and use in children of tyrosine kinase inhibitors and the ability to monitor and understand the prognostic significance of minimal residual disease by standardized molecular techniques has shifted the management of this condition from bone marrow transplantation as the main therapeutic modality to individualized treatment for each patient based on achieving specific milestones. The physiological changes occurring during childhood, particularly those affecting growth and development and the long-term use of treatment, pose specific challenges in this age group, which we are only beginning to understand.
British Journal of Haematology 06/2014; 167(1). DOI:10.1111/bjh.12977 · 4.71 Impact Factor
"However, TKIs are ineffective in patients who undergo blastic transformation, and unable to eradicate CML at the stem cell level. Moreover, often clinical drug resistance can develop through the acquisition of BCR-ABL gene mutations , . Given the promising in vitro results recently obtained with newly-shaped small molecules , in this study a systems biology approach was applied to assess global protein expression changes and targeted protein pathways upon treatment of K562 cells with the compounds IND_S1, MEL_T1, IND_S7 and MEL_S3. "
[Show abstract][Hide abstract] ABSTRACT: Over the past years, we synthesized a series of new molecules that are hybrids of spirocyclic ketones as complexity-bearing cores with bi- and ter-phenyls as privileged fragments. Some of these newly-shaped small molecules showed antiproliferative, pro-apoptotic and differentiating activity in leukemia cell lines. In the present study, to investigate more in depth the mechanisms of action of these molecules, the protein expression profiles of K562 cells treated with or without the compounds and were analyzed using two-dimensional gel electrophoresis coupled with mass spectrometry. Proteome comparisons revealed several differentially expressed proteins, mainly related to cellular metabolism, chaperone activity, cytoskeletal organization and RNA biogenesis. The major results were validated by Western blot and qPCR. To attempt integrating findings into a cellular signaling context, proteomic data were explored using MetaCore. Network analysis highlighted relevant relationships between the identified proteins and additional potential effectors. Notably, qPCR validation of central hubs showed that the compound induced high mRNA levels of the transcriptional factors EGR1 and HNF4-alpha; the latter to our knowledge is reported here for the first time to be present in K562 cells. Consistently with the known EGR1 involvement in the regulation of differentiation along megakaryocyte lineage, -treated leukemia cells showed a marked expression of glycoprotein IIb/IIIa (CD41) and glycoprotein Ib (CD42), two important cell markers in megakaryocytic differentiation, together with morphological aspects of megakaryoblasts and megakaryocytes.
PLoS ONE 02/2013; 8(2):e57650. DOI:10.1371/journal.pone.0057650 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The use of the polymerase chain reaction (PCR) was a revolutionary step in molecular biology, allowing for small amounts of genetic material to be amplified and studied. The advent of real-time PCR was a further refinement that led to reliable quantification of RNA and DNA. This allowed response monitoring and the detection of minimal residual disease, which proved to have important correlations with outcome in certain malignancies. The technology is indispensable for physicians and pathologists caring for oncology patients. In this article we will review the applications of molecular technology in the diagnosis and management of malignancies. Using chronic myeloid leukaemia (CML) as an example, technical aspects and clinical correlations will be discussed, with emphasis on the importance of quality assurance and standardisation to allow for comparability of results across laboratories. We will also examine emerging technologies that allow for high throughput and rapid turnaround of specimens and speculate how these would affect outcomes in future health care. The established and emerging molecular technologies have applications in many fields of oncology.
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