Dasatinib (Sprycel)

by Stephen Western
Astrocytoma Options.com

Dasatinib (trade name Sprycel, manufactured by Bristol-Myers Squibb) is an oral tyrosine kinase inhibitor, FDA approved in June 2006 for the treatment of chronic myelogenous leukemia and acute lymphoblastic leukemia (1). Dasatinib is currently being tested in two randomized phase II clinical trials for glioblastoma. Most relevant to glioblastoma therapy, the drug is an inhibitor of Src family kinases (SFKs), several of which are critical to glioblastoma cell migration.

Preclinical studies

In one cell culture study (2), a modest concentration of dasatinib (50 nanomolar) decreased invasion of two glioblastoma cell lines by approximately 50% in a Transwell migration assay. In this study, the combination of dasatinib with temozolomide synergistically increased cell cycle disruption and autophagic cell death, though the concentration of dasatinib used in this assay (200 nanomolar) exceeds physiological levels (100 nanomolar or less).

A second cell culture study (3) found that a 100 nanomolar (nM) concentration of dasatinib decreased Transwell migration by 71% (mean) in a panel of six glioma cell lines. There was no decrease in cell viability at this concentration. The combination of 100 nanomolar dasatinib with 100 nM of the experimental STAT3 inhibitor JSI-124 reduced cell proliferation of two glioma cell lines by about 50% compared to controls. The interaction of these two agents was found to be synergistic. This combination had minimal effect of normal human astrocytes.

A third cell culture study (4) found that a clinically achievable concentration of dasatinib (100 nM) reduced the invasion of U87 glioblastoma cells by 85% compared to untreated control cells after six hours. Under these conditions, activation of Src family kinases and focal adhesion kinase (FAK), both of which are involved in the formation of focal adhesions during cell migration, was inhibited. The localization of important integrin receptors was also disrupted by dasatinib. In the same study, immunodeficient mice were injected with U87 glioblastoma cells in the shoulder, and the tumors were grown to a size of 6 mm. Oral dasatinib was then administered for ten days, at which time animals treated with dasatinib had a tumor volume reduction of 83% compared to untreated control animals. It must be noted that the daily dasatinib doses used in this study (72-95 mg per kg body weight), after conversion to human-equivalent dose based on body surface area, were higher than that used in human trials.

While most conventional chemotherapeutic drugs act by causing toxicity to dividing cells, there are few effective drugs which prevent glioma migration into healthy brain tissue. And while anti-angiogenic drugs which target tumor blood vessels, such as bevacizumab (Avastin), may slow tumor growth in the short-term, the tumor typically responds to this strategy by increasing invasiveness. The overall benefit of anti-angiogenic drugs such as Avastin is therefore limited by the resulting increase in tumor migration and invasion into normal brain tissue.

One of the most promising uses of dasatinib is in conjunction with bevacizumab (Avastin). A recent study with mice showed that dasatinib has the ability to significantly (though not completely) limit the bevacizumab-induced increase in invasive behaviour in experimental glioblastoma. In this study (5), Src family kinase (SFK) activity was shown to be increased at the infiltrating edge of invasive glioblastomas in mice. SFK activity was further increased following treatment with bevacizumab (Avastin). Non-invasive GBM10 glioblastoma cells were implanted into mouse brains. The tumors were allowed to grow for two weeks, followed by 19 days of either bevacizumab alone or bevacizumab plus oral dasatinib (30 mg per kg body weight, two times per day). The number of GBM10 cells invading into normal brain tissue was increased approximately 4.5-fold compared to the untreated control group (Figure 5B of the published study). The combination of oral dasatinib and injected bevacizumab reduced the number of invading cells to approximately 2-fold compared to untreated controls. The bevacizumab-induced intensification of invasion was therefore impressively limited, though not eliminated, in this glioblastoma model. The dasatinib dosage used in this study, after conversion to human-equivalent dose based on body surface area, was somewhat higher than the maximum tolerated dose in humans (about 200 mg per day).

Human trials

Several phase I clinical trials of dasatinib in combination with other agents (such as erlotinib or lomustine) for recurrent gliomas have been carried out. Phase I trials are designed to determine safety and toxicity profiles, rather than efficacy. A phase II trial of dasatinib for recurrent glioblastoma or gliosarcoma patients was carried out with a primary completion date of March 2011, but has not yet published results. Two large randomized phase II trials of dasatinib in combination with other agents are currently (as of December 2013) recruiting participants. One of these is testing the combination of bevacizumab (Avastin) and dasatinib for recurrent glioblastoma, with an estimated primary completion date of June 2014. The other is testing dasatinib in combination with standard radiation therapy and temozolomide for newly diagnosed glioblastoma, with an estimated primary completion date of September 2013. A confirmation of the efficacy of dasatinib for glioblastoma patients awaits publication of the results of these three phase II trials.

Increasing dasatinib efficacy

An interesting study with mice (6) demonstrated that dasatinib concentrations in the brain are inhibited by the two drug efflux pumps P-glycoprotein (ABCB1) and breast cancer reistance protein (BCRP/ABCG2) which function together at the blood-brain barrier. When the experimental dual P-glycoprotein-BCRP inhibitor elacridar was administered to mice, brain concentrations of intravenous dasatinib were increased 10-fold compared to the control mice without elacridar. Other clinically used drugs or supplements which inhibit P-glycoprotein and BCRP, such as disulfiram and EGCG (green tea extract) will be discussed in the Blood-Brain Barrier article.

References

1. FDA approval for Dasatinib
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2. Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma. Milano et al. 2009.
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3. Dasatinib synergizes with JSI-124 to inhibit growth and migration and induce apoptosis of malignant human glioma cells. Premkumar et al. 2010.
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4. Noninvasive imaging of alphaVbeta3 function as a predictor of the antimigratory and antiproliferative effects of dasatinib. Dumont et al. 2009.
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5. Targeting Src family kinases inhibits bevacizumab-induced glioma cell invasion. Huveldt et al. 2013.
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6. Brain accumulation of dasatinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by elacridar treatment. Lagas et al. 2009.
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This page was created on 12/24/2013 and last updated on 04/21/2019