AV-65, a novel Wnt/β-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model

Yao, Hisayuki; Ashihara, Eishi; Strovel, Jeffrey; Nakagawa, Yoko; Kuroda, Junya; Nagao, Rina; Tanaka, Ray; Yokota, Asumi; Takeuchi, Miki; Hayashi, Yoshihiro; Shimazaki, Chihiro; Taniwaki, Masafumi; Strand, Kathryn; Padia, Janak; Hirai, Hideyo; Kimura, Shinya; Maekawa, Taira

doi:10.1038/bcj.2011.41

Cited by 43 publications

(30 citation statements)

References 37 publications

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“…The Wnt/β-catenin signaling pathway is well known to modulate cell differentiation, proliferation and apoptosis. The roles of the Wnt pathway in the pathogenesis of MM have received increasing attention recently (31–33). To determine whether Wnt/β-catenin signaling defect is responsible for decreasing multiple myeloma cell growth in the absence of gp96, we compared the canonical Wnt signaling between empty vector (EV) control and gp96 KD RPMI 8226 cells by western blot.…”

Section: Resultsmentioning

confidence: 99%

“…Our study has added significantly to the emerging role of Wnt signaling in MM (31–33). Human MM cells appear to have hallmarks of active Wnt signaling by overexpressing β-catenin which promotes proliferation of multiple myeloma (46).…”

Section: Discussionmentioning

confidence: 99%

“…Human MM cells appear to have hallmarks of active Wnt signaling by overexpressing β-catenin which promotes proliferation of multiple myeloma (46). Furthermore, blocking β-catenin with small-molecule inhibitors, AV-65 (33) or PKF115-584 (31, 32) specifically inhibits MM cell proliferation. Paradoxically, higher expression of Wnt signaling inhibitor, Dickkopf1 (Dkk1) in bone marrow stromal cells can promote myeloma growth (47).…”

Section: Discussionmentioning

confidence: 99%

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Molecular Chaperone gp96 Is a Novel Therapeutic Target of Multiple Myeloma

Hua

White‐Gilbertson

Kellner

et al. 2013

Clinical Cancer Research

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Purpose gp96 (grp94) is a key downstream chaperone in the ER to mediate unfolded protein response (UPR) and the pathogenesis of multiple myeloma (MM) is closely linked to dysregulated UPR. In this study, we aimed to determine the roles of gp96 in the initiation and progression of MM in vivo and in vitro. Experimental design We generated a mouse model with over-expression of XBP1s and conditional deletion of gp96 in B cell compartment simultaneously to identify the roles of gp96 in the development of MM in vivo. Using a shRNA system, we silenced gp96 in multiple human MM cells and examined the effect of gp96 knockdown on MM cells by cell proliferation, cell cycle analysis, apoptosis assay, immunohistochemistry and human myeloma xenograft model. The anti-cancer activity of gp96 selective inhibitor, WS13 was evaluated by apoptosis assay and MTT assay. Results Genetic deletion of gp96 in XBP1s-Tg mice attenuates multiple myeloma. Silencing of gp96 causes severe compromise in human MM cell growth through inhibiting Wnt-LRP-survivin pathway. We also confirmed that knockdown of gp96 decreased human MM growth in a murine xenograft model. The targeted gp96 inhibitor induced apoptosis and blocked MM cell growth, but did not induce apoptosis in pre-B leukemic cells. We have demonstrated that myeloma growth is dependent on gp96 both genetically and pharmacologically. Conclusions gp96 is essential for MM cell proliferation and survival, suggesting that gp96 is a novel therapeutic target for multiple myeloma.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Molecular Chaperone gp96 Is a Novel Therapeutic Target of Multiple Myeloma

Hua

White‐Gilbertson

Kellner

et al. 2013

Clinical Cancer Research

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“…In addition, AV65 and artificial F-box are agents that have preclinical antineoplastic activity via a similar mechanism. 157,158 …”

Section: Targeting the Wnt Pathwaymentioning

confidence: 99%

Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update

et al. 2015

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During the past decade, cancer stem cells (CSCs) have been increasingly identified in many malignancies. Although the origin and plasticity of these cells remain controversial, tumour heterogeneity and the presence of small populations of cells with stem-like characteristics is established in most malignancies. CSCs display many features of embryonic or tissue stem cells, and typically demonstrate persistent activation of one or more highly conserved signal transduction pathways involved in development and tissue homeostasis, including the Notch, Hedgehog (HH), and Wnt pathways. CSCs generally have slow growth rates and are resistant to chemotherapy and/or radiotherapy. Thus, new treatment strategies targeting these pathways to control stem-cell replication, survival and differentiation are under development. Herein, we provide an update on the latest advances in the clinical development of such approaches, and discuss strategies for overcoming CSC-associated primary or acquired resistance to cancer treatment. Given the crosstalk between the different embryonic developmental signalling pathways, as well as other pathways, designing clinical trials that target CSCs with rational combinations of agents to inhibit possible compensatory escape mechanisms could be of particular importance. We also share our views on the future directions for targeting CSCs to advance the clinical development of these classes of agents.

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“…It was shown that AV-65, a novel Wnt/ β -catenin signal inhibitor, successfully suppressed progression of MM [38]. Myeloma cells suppress osteoblast differentiation by secreting Wnt signaling inhibitors such as dickkopf 1 (DKK1) and soluble frizzled receptor-like proteins (sFRPs) [39].…”

Section: Wnt Notch and Hedgehog (Hh) Pathway Inhibitorsmentioning

confidence: 99%

Molecularly Targeted Therapies in Multiple Myeloma

Puente

Muz

Azab

et al. 2014

Leukemia Research and Treatment

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Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients will eventually relapse or become refractory to the treatments. Although the treatments have improved, the major problem in MM is the resistance to therapy. Novel agents are currently in development for the treatment of relapsed/refractory MM, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, cell signaling targeted therapies, and strategies targeting the tumor microenvironment. We have previously reviewed in detail the contemporary immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies therapies for MM. Therefore, in this review, we focused on the role of molecular targeted therapies in the treatment of relapsed/refractory multiple myeloma, including cell signaling targeted therapies (HDAC, PI3K/AKT/mTOR, p38 MAPK, Hsp90, Wnt, Notch, Hedgehog, and cell cycle) and strategies targeting the tumor microenvironment (hypoxia, angiogenesis, integrins, CD44, CXCR4, and selectins). Although these novel agents have improved the therapeutic outcomes for MM patients, further development of new therapeutic agents is warranted.

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AV-65, a novel Wnt/β-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model

Cited by 43 publications

References 37 publications

Molecular Chaperone gp96 Is a Novel Therapeutic Target of Multiple Myeloma

Molecular Chaperone gp96 Is a Novel Therapeutic Target of Multiple Myeloma

Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update

Molecularly Targeted Therapies in Multiple Myeloma

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