Emerging data on new drugs

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There is also emerging data on some of the new drugs under development

suggesting that these recalcitrant clones can be inhibited. BMS-214662, a

cytotoxic farnesyltransferase inhibitor (FTI), has been shown to target

primitive progenitor cells (PPC) in CML.[25] In long-term culture-initiating

cell (LTC-IC) assays with both chronic-phase CML and normal CD34+ progenitors,

addition of BMS-214662 to dasatinib in vitro has been shown to dramatically

reduce the PPC colonies and also overcome kinase domain mutation transfectants

in Baf3 cell lines.

http://www.medscape.com/viewarticle/576209_6

Development of some new kinase inhibitors are able to override resistance to

imatinib. Based on data from recently published clinical trials of dasatinib

(BMS-354825) and nilotinib (AMN107) it is obvious that neither of these agents

will be beneficial in patients with the T315I mutation either.

http://www.medscape.com/viewarticle/576209_7

(AMN107), and the Src/Abl inhibitors, such as dasatinib (formerly BMS-354825),

AP23464, bosutinib and PD166326 are called the Sons of Iminatib, as they are

also multi-targeted.

http://www.medscape.com/viewarticle/576209_8

Bosutinib (SKI-606; Wyeth, NJ, USA) is an orally available, dual Src/Abl kinase

inhibitor shown to be 200-fold more potent than imatinib as an inhibitor of

bcr-abl phosphorylation in biochemical assays.

http://www.medscape.com/viewarticle/576209_9

Competitive inhibitors of Bcr-abl are Aurora Kinase Inhibitors. Aurora kinases

are a family of serine/threonine kinases that are essential for protein

phosphorylation events regulating the mitotic progression of the cell cycle.

The investigation of Aurora kinase inhibitors as potential therapeutic agents in

cancer is based on the fact that Aurora kinases are overexpressed in various

human cancers. PHA-739358, which is currently tested in clinical trials, has

great therapeutic potential in anticancer therapy in a wide range of cancers.

The compound has significant antitumor activity in different xenografts and

spontaneous and transgenic animal tumor models and shows a favorable

pharmacokinetic and safety profile. This drug currently being tested in

clinical trials has great therapeutic potential in anticancer therapy in a wide

range of cancers. Most frequent side effects include fatigue, anorexia,

nausea, vomiting, diarrhea, constipation and pyrexia.

http://mct.aacrjournals.org/cgi/content/abstract/6/12/3158

ON012380 (Onconova Therapeutics, PA, USA) inhibits the kinase activity by a

non-ATP competitive allosteric mechanism, which involves bcr-abl inhibition by

interacting with the substrate-binding sites of the protein kinases, rather than

involving the ATP binding site.[63] In mice, it causes regression of leukemias

induced by injection of cells expressing the most resistant T315I mutant, by

promoting apoptosis of bcr-abl and mutant bcr-abl-expressing cells with an IC50

in the nanomolar range. However, the drug has not yet entered clinical trials.

http://www.medscape.com/viewarticle/576209_10

Monitoring Disease responses: As most patients are able to achieve complete

cytogenetic responses with tyrosine kinase inhibitors (TKIs), sensitive and

accurate monitoring of bcr-abl is required to measure residual disease. In CML

patients who achieved a complete cytogenetic response, fluorescence in situ

hybridization (FISH) is more sensitive than conventional cytogenetics to monitor

Ph negativity, and thus a biologic response to treatment Since FISH studies

typically involve looking for the bcr-abl fusion fluorescence in at least 200

interphase cells, this precludes the sensitivity of FISH in making judgments on

the extent of residual disease. Furthermore, since most CML studies have

assessed long-term outcomes by monitoring cytogenetics and not FISH,

quantitative RT-PCR (qRT-PCR) is currently used for assessing the depth of the

molecular response and measurement of residual disease with a sensitivity of up

to 10. Molecular remission can thus be defined in this fashion as a reduction

in the quantification of bcr-abl transcripts to an undetectable level, and can

be considered as a surrogate marker for cure and/or long-term disease control.

http://www.medscape.com/viewarticle/576209_5

Role of Measurement in residual disease: The presence of minimal residual

disease in patients treated with imatinib mesylate may be due to the reservoir

of disease, the diseased quiescent hematopoietic stem cell (HSC) subpopulation

(which is approximately 0.5% of Ph+ HSC population) present within the cells,

insensitive to imatinib mesylate therapy. The etiology of disease 'persistence'

(residual disease) at the molecular level may be multifactorial. There is also

emerging data on some of the new drugs under development suggesting that these

recalcitrant clones can be inhibited. BMS-214662, a cytotoxic

farnesyltransferase inhibitor (FTI), has been shown to target primitive

progenitor cells (PPC) in CML. http://www.medscape.com/viewarticle/576209_6

Blessings,

Lottie