pidly induce ubiquitination of BCR-ABL resulting in protein relocation into aggresomes, rendering it inactive. Both imatinib-sensitive and – resistant CML cells initiated apoptosis in response to WP1130.97 Hsp90 inhibitors geldanamycin and 17-AAG were shown to induce degradation of BCR-ABL protein in vitro.98,99 Ecdysone Mechanistically, following dissociation of Hsp-90 from client proteins, Bag1 , mediates BCR-ABL localization to the proteasome and stimulates its degradation via an E3-ligase-dependent mechanism.100 However, clinical trials in CML were disappointing. Immunotherapy In addition to small molecules, immunologic targeting of BCR-ABL, rather than kinase inhibition, may be effective. IFN may function by inducing cytotoxic T cell responses against myeloid antigens.
101 A more specific approach is vaccines targeting the BCR-ABL junction.102,103 Despite some encouraging results, the efficacy of this approach remains Woessner et al. Page 7 Cancer J. Author manuscript, available in PMC 2012 May 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript RAD001 159351-69-6 unproven in the absence of a prospective randomized trial. Antibodies to the BCR-ABL junction have also been produced.104,105 Updates to these are smaller fragments of antibodies such as iDabs,106 including those specific to BCR-ABL,107 and small antibody mimics, or monobodies.108 The clinical utility of these antibodies is unclear. Targeting CML Stem Cells and Their Microenvironment The Stem Cell Niche In vitro, TKIs are known to have antiproliferative effects on primitive CML cells, but they do not induce apoptosis.
This may explain why TKIs fail to eliminate CML stem cells in vivo, evident by disease persistence and the inability to discontinue therapy. We have reported that primitive human CML stem cells are not dependent on BCR-ABL, suggesting that upon TKI challenge CML stem cells rely on survival signals other than BCR-ABL. It is likely that these signals are provided by the microenvironment. It follows that therapies which only biochemically target BCR-ABL will be unable to eliminate CML stem cells.71 Cytokines, chemokines, and the extracellular matrix, collectively referred to as the microenvironment, may activate signaling pathways involved in survival. Therapeutic strategies that target stem cells within this context hold promise to eliminate residual leukemia, including cytokine antagonists, adhesion molecule antagonists, and inhibitors of survival and self-renewal.
109 The Hedgehog signaling pathway has been implicated in hematopoietic stem cell renewal. Consistent with a critical role of Hh for CML pathogenesis, lack of Smoothened, an essential component of the pathway, was shown to attenuate CML in murine models.110 Similarly, the hedgehog inhibitor LDE225 in combination with nilotinib resulted in elimination of CML stem and progenitor cells.111 Several Hedgehog inhibitors, including PF-04449913, for hematological malignancies are also in clinical development.112 Wnt/-catenin signaling has also been shown to play a critical role in hematopoietic stem cell selfrenewal and may offer therapeutic opportunities.
113 AKT, a well-established downstream target of BCR-ABL, phosphorylates the Foxo3a transcription factor, leading to its exclusion from the nucleus and suppression of transcription. Despite this, Foxo3a is nuclear in primitive CML cells. Recent data have suggested that TGF- signaling may be responsible for this unexpected finding, and it has been inferred that this may allow CML stem cells to remain in a quiescent state, despite BCR-ABL activity. If so, this would suggest that inhibiting TGF- may push the critical cells into cycle, thereby rendering them susceptible to BCR-ABL inhibition. Efficient depletion of CML in vivo was found with a combinati