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CXCR4 up-regulation by imatinib induces chronic myelogenous leukemia (CML) cell migration to bone marrow stroma and promotes survival of quiescent CML cells

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#1 valiantchong


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Posted 02 September 2011 - 01:26 PM


Wondering any treatment could help to improve the situation ?

Imatinib-induced CXCR4 mediates CML cell migration and adhesion in bone marrow niche. Bcr-Abl specifically inhibits CXCR4 expression in CML cells, which is restored by Bcr-Abl tyrosine kinase inhibitors (i.e., imatinib). SDF-1 produced by bone marrow triggers CXCR4-expressing CML cells to extravasate and migrate across vascular wall. CXCR4 levels are further induced in migrating CML cells within cytokine-rich bone marrow milieu. Interactions of stroma-produced SDF-1 with CXCR4 trigger integrin engagement and activation of the downstream prosurvival pathways, such as ILK. CML cells intimately attach to stromal cells, which induce quiescence and ultimately chemoresistance of dormant CML progenitor cells

#2 Happycat


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Posted 02 September 2011 - 07:29 PM

There are other CXCR4-targeted drugs out there.  AMD3100 blocks CXCR4.  It looks to be the first generation CXCR4 drug, and AMD3465 would be their 2nd generation drug if successful.  AMD3100 is Plerixafor(?) - google AMD3100, you'll find it.  It is being used to induce stem cells to migrate out of the bone marrow for patients undergoing stem cell transplants.  So, yes, in theory it might be possible to shake those LSC out of their hidey-holes using a drug like AMD3100.  AMD3100 was originally developed to treat AIDS, but was not orally bioavailable enough (it's injected instead).

Here's another abstract on AMD3465, definitely more potent than AMD3100.

1826 The Effect of the CXCR4 Inhibitors, AMD3100 and AMD3465, in Multiple Myeloma Cell Homing and Its Interaction with the Bone Marrow Microenvironment

Oral and Poster Abstracts
Poster Session: Myeloma - Biology and Pathophysiology, excluding Therapy Poster I
Saturday, December 5, 2009, 5:30 PM-7:30 PM
Hall E (Ernest N. Morial Convention Center)
Poster Board I-848

Judith M. Runnels, PhD1, Abdel Kareem Azab, Bpharm, PhD1, Costas Pitsillides, PhD2*, Jonathan Farag3*, Juwell Wu2*, Aldo M. Roccaro, MD, PhD3, Patricia Maiso, PhD4*, Charles P. Lin, PhD2* and Irene M. Ghobrial, M.D.3

1Medical Oncology, Dana-Farber Cancer Inst., Boston, MA
2Advanced Microscopy Program, Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA
3Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
4Medical Oncology, Dana Farber Cancer Institute, Boston, MA

Patients with multiple myeloma (MM) typically present with the disease spread diffusely throughout the bone marrow (BM). This fact points to the role MM cell trafficking plays in disease progression. Like normal plasma cells, MM cell trafficking is directed by the cytokine, SDF-1 and its receptor, CXCR4. Using the small bicyclam molecule, AMD3100, to block the SDF-1/CXCR4 interaction, and in vivo flow cytometry to measure circulation time of MM cells in a xenograft model, we have previously shown that homing of injected AMD3100-treated MM cells to the bone marrow is perturbed. Soon after injection fewer AMD3100-treated than untreated MM cells are detected in mouse skull BM using in vivo fluorescence confocal microscopy. Furthermore, the combined treatment of established tumors with AMD3100 and bortezomib enhanced survival. Here we present data that the 2nd generation SDF-1/CXCR4 small monomacrocyclic inhibitor, AMD3465 behaves like its predecessor in blocking antibody binding to CXCR4 on MM cells, migration of MM cells toward SDF-1, and in vivo homing, but at concentrations 10-50 fold lower than AMD3100. Incubation with either 1uM AMD3465 or 50uM AMD3100 reduced antibody binding to CXCR4 on MM cells to isotype control levels. Likewise, treatment with AMD3465 reduced MM1S migration to 15% of that of untreated cells in a transwell migration assay. These in vitro effects translated in vivo into longer circulation times for AMD3465-treated MM cells than control cells. In vivo flow cytometry revealed that 40-50% of AMD3465-pre-treated cells remained in the circulation one hr after injection whereas untreated cells depleted to 20% of their original circulating cell count by that time. Future experiments will further describe the effect of AMD 3465 on MM cells in the BM microenvironment to answer whether AMD3465 can be used to mobilize MM cells from the BM environment or enhance survival when used in conjunction with therapeutic drugs.

#3 valiantchong


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Posted 02 September 2011 - 10:59 PM

Thank you for the information, wondering is any trial is use for CML treatment successfully....and if this case is true, then STIM trial will probably not last if this treatment is not included.

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