I wrote about a potential of therapeutic targeting so-called “cancer stem cell niche” while ago. I was always interested in role and potential targeting of leukemia-initiating cells microenvironment in bone marrow. Because of some new data came out of ASH annual meeting, I decided to keep you updated. I summarize the most interesting current and previous findings in leukemic stem cell niche targeting in the table below.
Basically, targeting of cancer stem cell environment focus on few mechanisms – adhesion and mobilization, cell cycle, hypoxia and angiogenesis.
Although the full nature of LIC-niche interaction remains elusive, it has been postulated as a useful target for leukemia therapy based on a dual rationale: on one hand, the survival of LICs may depend upon interactions with specific niche, while on the other hand, chasing LICs out of the BM niche may drive quiescent LICs into active cell cycle, sensitizing them for conventional chemotherapy.
The top part of table represent new targets, reported this year. The low part represent “old targets”. some of which have entered clinical trials.
| potential agent |
target |
mechanism |
reference |
| CASIN | Cdc42 | GTPase, selective mobilization of leukemia-initiating cells |
ASH’09 abstract |
| PR-104 | HIF-1α | under hypoxia, reduced to hydroxylamine and amine metabolites that in turn induce DNA cross-links and cell death | ASH’09 abstract |
| BBGC | Glo-1 | disrupt glycolysis in hypoxia-adapted quiescent leukemic cells |
ASH’09 abstract |
| AMD3465 and AMD3100 (Mozobil) |
CXCR4 | blocking LSC homing to a BM niche, mobilize and/or sensitizing leukemic cells to chemotherapy | Blood 2009;113:6215 |
| LY294002 or QLT0267 | integrin-linked kinase (ILK) | inhibition of stroma-induced phosphorylation of Akt and GSK3β and other signaling pathways | Cancer Res 2007;67:684 |
| bevacizumab (anti-VEGF antibody) | VEGF | binding and inactivation of VEGF | Clin Cancer Res 2004;10:3577 |
| anti-VLA4 antibody | VLA-4 | Interrupt adhesion of leukemic cells to stromal cells |
Nat Med 2003;9:1158 |
| anti-CD44 antibody | CD44 | Interrupt adhesion of leukemic cells to niche cells | Nat Med 2006;12:1167 |
One thing I didn’t get – How leukemic stem cell niche withing bone morrow in one hematological malignancy could be hypoxic and vascular in the same time? Let’s say if AML stem cells survival highly depends on hypoxia, targeting of this mechanism could succeed, but not targeting of vascularisation/angiogenesis.
Also read: The leukemic stem cell niche: current concepts
New insights into leukemic microenvironment in bone marrow
Therapeutic targeting of microenvironmental interactions in leukemia: Mechanisms and approaches
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Connotea tags: cancer stem cell niche
Related posts:
- The leukemic stem cell niche: current concepts
- Possible anti- cancer stem cell effects of well known drugs
- Targeting of signaling pathways in leukemia and conditioning for bone marrow transplant
- Target cancer stem cells, if there is any
- Reviews: Right on target: eradicating leukemic stem cells by Daniela Krause & Richard Van Etten
{ 1 comment… read it below or add one }
A little irrelevant, there’s a recent article that discusses how HIF2 is a central axis common to many tumor types (http://www.pnas.org/content/106/50/21306.short?rss=1). Seems like drugs that target this TF will be particularly potent. HIF2 is of course differentially expressed from HIF1. I don’t have a lot of knowledge about HIF1. Is HIF1 a common axis in blood disorders? If so, it’s a better target than others for drug development.