Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Introduction: Significant advances have been made during the last two decades in terms of new therapeutic options but also of innovative approaches to diagnosis and management of multiple myeloma (MM). While patient survival has been significantly prolonged, most patients relapse. Including the milestone approval of the first kinase inhibitor imatinib mesylate for CML in 2001, 48 small molecule protein kinase (PK) inhibitors have entered clinical practice until now. However, no PK inhibitor has been approved for MM therapy yet. Areas covered: This review article summarizes up-to-date knowledge on the pathophysiologic role of PKs in MM. Derived small molecules targeting receptor tyrosine kinases (RTKs), the Ras/Raf/MEK/MAPK- pathway, the PI3K/Akt/mTOR- pathway as well as Bruton tyrosine kinase (BTK), Aurora kinases (AURK), and cyclin-dependent kinases (CDKs) are most promising. Preclinical as well as early clinical data focusing on these molecules will be presented and critically reviewed. Expert opinion: Current MM therapy is directed against general vulnerabilities. Novel therapeutic strategies, inhibition of PKs in particular, are directed to target tumor-specific driver aberrations such as genetic abnormalities and microenvironment-driven deregulations. Results of ongoing Precision Medicine trials with PK inhibitors alone or in combination with other agents are eagerly awaited and hold the promise of once more improving MM patient outcome.
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PMID:Emerging protein kinase inhibitors for the treatment of multiple myeloma. 3132 78

The anticancer drug dasatinib (Sprycel) is a BCR-ABL1-targeted tyrosine kinase inhibitor used in treating chronic myelogenous leukemia that has been shown in clinical trials to display cardiovascular toxicities. While dasatinib potently inhibits BCR-ABL1, it is not a highly selective kinase inhibitor and may have off-target effects. A neonatal rat cardiac myocyte model was used to investigate potential mechanisms by which dasatinib damaged myocytes. The anthracycline cardioprotective drug dexrazoxane was shown to be ineffective in preventing dasatinib-induced myocyte damage. Dasatinib treatment increased doxorubicin accumulation in myocytes and doxorubicin-induced myocyte damage, likely through its ability to bind to one or more ABC-type efflux transporters. Dasatinib induced myocyte damage either after a brief treatment that mimicked the clinical situation, or more potently after continuous treatment. Dasatinib slightly induced apoptosis in myocytes as evidenced by increases in caspase-3/7 activity. Dasatinib treatment reduced pERK levels in myocytes most likely through inhibition of RAF, which dasatinib strongly inhibits. Thus, inhibition of the RAF/MEK/ERK pro-survival pathway in the heart may be, in part, a mechanism by which dasatinib induces cardiovascular toxicity.
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PMID:Mechanisms of the Cardiac Myocyte-Damaging Effects of Dasatinib. 3212 37

This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for chronic myeloid leukaemia targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies.
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PMID:Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society. 3246 67


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