No Successful Treatments for AML

The current treatments of AML patients are considered unsuccessful. Although a complete remission of adult AML is achieved by induction therapy using anthracyclins and cytarabine, the therapy eventually fails due to disease relapse. Moreover, due to the diversity of AML cytogenetics and molecular background, there is an increasing need for targeted therapy.

A panel of inhibitors against Flt3 as well as anti-Flt3 antibodies has been developed and is at present in different phases of clinical trials [189], [190], [191] and [192]. These are all small molecule heterocyclic compounds that competitively inhibit ATP binding to Flt3, but are not considered very specific. All reduce the cell proliferation rate by up regulating pro-apoptotic proteins but have had little effect in clinical studies. The therapeutic responses are usually modest with a transient reduction of peripheral blasts, and clinical trials are currently focused on combining Flt3 inhibitors with conventional chemotherapy. Most of the Flt3 inhibitors are rather unspecific like the majority of kinase inhibitors in general, and often recognize targets like PDGFR, c-Kit and VEGFR. This not only disables the evaluation of Flt3 inhibition, but may cause toxic responses due to the multiple targets when used in patients. Recently, a novel type of kinase inhibitor LS104, competing out substrate binding to the receptor instead of inhibiting the ATP binding site, was shown to target Flt3 ITD and its downstream signaling in primary AML blasts [193]. There have been reports of anti-Flt3 neutralizing antibodies in leukemic mouse models with positive responses [194], and this approach is more specific and less toxic. The antibodies mainly interfered with the cell surface expressed Flt3,...

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...similar mechanism as in CML might in part explain this. Indeed, levels of RAD51 have been positively correlated to Stat5 activation in Flt3 ITD expressing Ba/F3 cells, and the use of the Flt3 inhibitor PKC412 reduced the expression of the RAD51 transcript [202]. In a gene expression study of relapsed AML patients, the leukemic blasts showed an increased proliferation due to enhanced activation of Raf, Mek and Erk, most likely caused by upstream oncogenic events [203]. It has further been demonstrated that Flt3 ITD positive patients also lacking the Flt3 wild-type (wt) allele have a significantly shortened survival when compared to those with Flt3 ITD/wt or wt alone. These patients were found in about 35% of the cases with an Flt3 ITD allele [204]. One theory is that the presence of the wild-type Flt3 compensates for some of the oncogenic effects of the ITD receptor.