Steven Grant, MD
2010-04-27
Dr. Grant indicated no relevant
conflicts of interest.
Naka K, Hoshii T, Muraguchi T, et al. TGF-beta-FOXO
signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature.
2010;463:676-80.
The introduction of the Bcr/abl kinase inhibitor imatinib mesylate
(Gleevec) revolutionized treatment of CML and represents the prototype of
molecularly targeted therapy. However, while imatinib continues to produce impressive
clinical results, aside from a subset of patients who are eligible for stem
cell transplantation, essentially all CML patients ultimately progress and die.
This often reflects the development of Bcr/abl mutations or other forms of
resistance. There is also speculation that while imatinib and other kinase
inhibitors may eradicate the large majority of CML cells, they may permit CML stem
cells to survive. This notion is supported by preclinical evidence that various
clinically relevant Bcr/abl kinase inhibitors do not efficiently induce cell
death in the most primitive CML stem cell compartment.1
Such considerations have
prompted intense interest in the development of strategies specifically
designed to eradicate CML stem cells. Some of these efforts have focused on
disruption of developmental pathways. For example, recent studies suggest that,
unlike imatinib, pharmacologic or genetic interruption of the hedgehog
signaling pathway depletes CML stem cells,2 raising the possibility that a
combined approach using Bcr/abl kinase inhibitors to eliminate the bulk of the
leukemic cells with agents capable of eradicating CML stem cells may lead to
improved therapeutic efficacy.
This article from the
laboratory of Atsushi Hirao at Kanazawa University suggests an alternative and
potentially complementary approach to eliminate CML stem cells. Akt is an
important Bcr/abl downstream signaling molecule which promotes survival by negatively
regulating Foxo family transcription factors. Using a murine syngeneic
transplantation model, Naka et al. showed that leukemia-initiating cells (LICs)
displayed diminished phosphorylation of Akt and increased nuclear localization
of Foxo3A. Transgenic mice deficient in Foxo3A exhibited a significant
impairment in the ability of LICs to induce disease, suggesting that Foxo3A
plays a critical role in the maintenance of CML LICs. In addition, they showed
that TGF-β negatively regulated Akt activation and thus promoted Foxo3A nuclear
localization. An approach combining pharmacologic TGF-β inhibition and imatinib
in the setting of Foxo3A deficiency was highly effective in eliminating CML
stem cells and eradicating disease in vivo.
These findings could
have significant implications for efforts to elucidate mechanisms responsible
for failure of conventional therapies to eradicate CML stem cells and may also
provide important insights into new therapeutic strategies to overcome this problem.
It is particularly interesting that activation of Akt, which is generally
thought to contribute to Bcr/abl-mediated survival signaling, may paradoxically
limit the maintenance of CML stem cells by suppressing Foxo3A. If validated, this
could explain why standard Bcr/abl kinase inhibitors display a very limited
capacity to eliminate the most primitive CML progenitor cells. Another important
implication of these findings is that in order to achieve durable responses,
and possibly cures, a multi-pronged approach targeting both stem cells and
their more differentiated progeny may be necessary. For example, future
chemotherapeutic approaches to this disease might involve co-administration of
a Bcr/abl kinase inhibitor, particularly one active against cells bearing
imatinib mesylate-resistant mutations, in conjunction with inhibitors of
pathways required for CML stem cell maintenance. In this context, Hedgehog
inhibitors have recently entered the clinical arena, and plans for such
combination regimens are currently underway. Although inhibitors of the TGF-β/Foxo
pathway are not yet in the clinic, studies such as the one by Naka et al. provide
a strong rationale for their development. Their arrival is awaited with much
anticipation.
- Copland M, Hamilton A,
Elrick LJ, et al. Dasatinib
(BMS- 354825) targets an earlier progenitor population than imatinib in primary
CML but does not eliminate the quiescent fraction. Blood. 2006;107:4532-39.
- Zhao C, Chen A,
Jamieson CH, et al. Hedgehog
signaling is essential for maintenance of cancer stem cells in myeloid
leukaemia. Nature. 2009;458:776-79.
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