10 Mar 2014
Researchers in Manchester have investigated the stickiness of leukaemia cells, and whether this is linked to drug resistance.
Chronic myeloid leukaemia (CML) is associated with a specific genetic mutation that results from DNA on different chromosomes breaking off and swapping places. This disrupts genes at the breakpoint and the rejoining point. One of these disrupted genes is called BCR-ABL and drugs that target this mutation have transformed the treatment of CML. However, patients can develop resistance to these drugs, which causes their cancer to return.
Now scientists from The University of Manchester – part of the Manchester Cancer Research Centre - have measured the levels of the BCR-ABL genetic mutation in a cell model of CML. In particular, they separated cells into those that stuck to plastic – “sticky”, or adherent, cells – and those non-adherent ones that did not, and looked for differences between the two groups of cells.
News | September 03, 2014 | Leukemia & Lymphoma, Chronic Myeloid Leukemia, Hematologic Malignancies
By Dave Levitan
STAT3 inhibition using a novel compound restored sensitivity to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) cells that had shown resistance independent of BCR-ABL1 kinase activity, according to a new study published in the journal Leukemia. The findings could help fill gaps in CML treatment for patients with unexplained resistance to TKIs.
Though TKIs have revolutionized the treatment of CML, between 20% and 30% of patients fail on imatinib due to primary or acquired resistance. “BCR-ABL1 point mutations fail to explain many cases of clinical TKI failure, as many patients with resistance express exclusively native BCR-ABL1,” wrote study authors led by Michael W. Deininger, MD, PhD, of Huntsman Cancer Institute at the University of Utah in Salt Lake City. In such patients where resistance is independent of BCR-ABL1, the researchers hypothesized that targeting the signal transducer and activator of transcription 3 (STAT3) pathway may eliminate that resistance.
The group used structure-activity relationship (SAR) studies and compound library screens to identify BP-5-087, “a potent and selective STAT3 inhibitor.” They confirmed that this molecule binds to the STAT3 SH2 domain using both computation simulations and hydrogen-deuterium exchange assays.
They then tested the effects of BP-5-087 on primary CML cells from newly diagnosed patients. In treatment-naive cells, it had little effect, but in combination with imatinib it reduced formation of cells by 56%. It also showed good activity along with imatinib in CML cells with intrinsic TKI resistance (meaning, independent of BCR-ABL1). The effect was seen in both CML progenitor cells and in leukemic stem cells. ...read more
Sustained inhibition of STAT5, but not JAK2, is essential for TKI-induced cell death in chronic myeloid leukemia
L Schafranek1,2,3, E Nievergall1,2,3, J A Powell4,5, D K Hiwase3,6, T Leclercq1,3, T P Hughes1,2,3,6,7 and D L White1,2,3,4
Kinase inhibitors block proliferative signals in BCR-ABL1+ leukemic cells, but their capacity to induce apoptosis is poorly understood. Initial studies suggested that very brief exposure to kinase inhibitors was sufficient to induce apoptosis in chronic myeloid leukemia (CML) cells. However, flaws in this experimental model have subsequently been identified, leading to the conclusion that apoptosis only occurs with sustained low-level kinase inhibition. Thus, the minimum duration of complete kinase inhibition required to commit CML cells to death is unknown. Here we confirm that <1 h is insufficient to induce significant commitment to death in BCR-ABL1+ cell lines and in primary CD34+ progenitor cells, and establish that commitment to cell death only occurs if kinase inhibition is maintained for 4 h or more. Remarkably, signal transducer and activator of transcription 5 (STAT5) inhibition in combination with transient (<1 h) tyrosine kinase inhibitor (TKI) exposure proved lethal for CML progenitors, despite the reactivation of Bcr-Abl after 1 h. JAK kinase inhibition did not induce cell death in combination with transient TKI exposure. Thus, STAT5 appears to be a critical determinant of the time-dependent sensitivity of CML progenitor cells to TKI treatment in a Bcr-Abl-dependent, but JAK-independent, manner. We conclude that combining kinase inhibition with STAT5 inhibition represents a promising therapeutic approach in BCR-ABL1+ leukemias.
Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: tyrosine-kinase inhibitor combinations and beyond
Wesam Ahmed and Richard A. Van Etten
Hematology 2013 2013:189-200; doi:10.1182/asheducation-2013.1.189
In patients with chronic myeloid leukemia (CML) in chronic phase who have achieved complete molecular remission on imatinib therapy, clinical trials from France and Australia have demonstrated that the majority experience prompt molecular relapse of their leukemia upon discontinuation of the drug, showing that long-term monotherapy with tyrosine kinase inhibitors is not curative in the majority of patients with CML. This has focused attention on strategies to eradicate residual disease in CML that is presumed to arise from malignant Ph+ stem cells, which should result in permanent cure and long-term leukemia-free survival. Here, we review the evidence that targeting CML stem cells will be of clinical benefit and discuss pharmacological and immunological approaches to accomplish this goal. Where possible, we link preclinical studies of CML stem cell biology to emerging results from clinical trials of agents that may target these cells.
Read full article here:
Conclusions and future directions: getting into the clinic ...read more
Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia
Carlo Gambacorti-Passerini1,*, Jorge E. Cortes2, Jeff H. Lipton3, Anna Dmoszynska4, Raymond S. Wong5, Victor Rossiev6, Dmitri Pavlov7, Karin Gogat Marchant8, Ladan Duvillié8, Navin Khattry9, Hagop M. Kantarjian2 andTim H. Brümmendorf10,11
Article first published online: 21 JUL 2014
Abstract ...read more
Megan Brooks July 25, 2014
With the rapid and widespread uptake of tyrosine kinase inhibitors (TKIs) in oncology over the past several years, serious drug–drug interactions are an "increasing risk," according a new report.
To guarantee the safe use of TKIs, "a drugs review for each patient is needed," write Frank G.A. Jansman, PharmD, PhD, from Deventer Hospital in the Netherlands, and colleagues in a review published in the July issue of the Lancet Oncology.
The review provides a comprehensive overview of known and suspected interactions between TKIs and conventional prescribed drugs, over-the-counter drugs, and herbal medicines.
Amina Haouala1, Nicolas Widmer1, Michel A. Duchosal2, Michael Montemurro3, Thierry Buclin1, and Laurent A. Decosterd1
Several cancer treatments are shifting from traditional, time-limited, nonspecific cytotoxic chemotherapy cycles to continuous oral treatment with specific protein-targeted therapies. In this line, imatinib mesylate, a selective tyrosine kinases inhibitor (TKI), has excellent efficacy in the treatment of chronic myeloid leukemia. It has opened the way to the development of additional TKIs against chronic myeloid leukemia, including nilotinib and dasatinib. TKIs are prescribed for prolonged periods, often in patients with comorbidities. Therefore, they are regularly co-administered along with treatments at risk of drug-drug interactions. This aspect has been partially addressed so far, calling for a comprehensive review of the published data. We review here the available evidence and pharmacologic mechanisms of interactions between imatinib, dasatinib, and nilotinib and widely prescribed co-medications, including known inhibitors or inducers of cytochromes P450 or drug transporters. Information is mostly available for imatinib mesylate, well introduced in clinical practice. Several pharmacokinetic aspects yet remain insufficiently investigated for these drugs. Regular updates will be mandatory and so is the prospective reporting of unexpected clinical observations.
Effect of imatinib therapy with and without turmeric powder on nitric oxide levels in chronic myeloid leukemia
Ghalaut VS1, Sangwan L, Dahiya K, Ghalaut PS, Dhankhar R, Saharan R.
Nitric oxide (NO) is involved in different stages of malignancies. Increased levels of NO have been reported in different leukemias. Imatinib is the preferred drug for the treatment of chronic myeloid leukemia (CML). Turmeric powder contains curcumin which has anti-leukemic property and also decreases NO synthesis. This study was conducted on fifty patients of CML divided into two groups, group A receiving imatinib alone and group B receiving turmeric powder along with imatinib for six weeks. Nitric oxide levels were estimated in these patients before and after receiving therapy and were analyzed statistically. Nitric oxide levels were found to be significantly decreased in both the groups, but more significantly in group B after receiving the respective treatments. Thus, curcumin acts as an adjuvant to imatinib in decreasing the NO levels and may help in the treatment of CML patients.
PMID: 21844132 [PubMed - indexed for MEDLINE]
MDR1 expression predicts outcome of Ph+ chronic phase CML patients on second-line nilotinib therapy after imatinib failure
M Agrawal1, B Hanfstein1, P Erben1, D Wolf2, T Ernst3, A Fabarius1, S Saussele1, D Purkayastha4, R C Woodman4, W-K Hofmann1, R Hehlmann1, A Hochhaus3 and M C Müller1
Nilotinib was able to impede proliferation of MDR1-overexpressing imatinib-resistant cells. High MDR1 gene expression might identify patients whose mode of imatinib resistance is essentially determined by increased efflux activity of MDR1 and therefore can be overcome by second-line nilotinib treatment.