Syndecan-1 (CD138) Suppresses Apoptosis in Multiple Myeloma by Activating IGF1 Receptor: Prevention by SynstatinIGF1R Inhibits Tumor Growth

Beauvais, DeannaLee M.; Jung, Oisun; Yang, Yang; Sanderson, Ralph D.; Rapraeger, Alan C.

doi:10.1158/0008-5472.can-16-0232

Cited by 55 publications

(81 citation statements)

References 57 publications

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“…Evidence of synergy between ibrutinib and the IMiD lenalidomide and the PI bortezomib has been observed in both MM patient cells and in MM cell lines, as evidenced by an increased cytotoxicity of malignant plasma cells (Rushworth et al , 2013). Additional preclinical data suggest that both BTK inhibitors and IMiDs target the clonogenic side populations of CD138 neg cells, which are capable of clonogenic growth, self‐renewal and differentiation into myeloma plasma cells (Yang et al , 2006; Jakubikova et al , 2011; Beauvais et al , 2016). Increased BTK expression in the CD138 neg side population cells is associated with clonogenic growth, increased expression of pluripotent/embryonic stem cell genes, and potential resistance to many standard myeloma treatments.…”

Section: Discussionmentioning

confidence: 99%

Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results

et al. 2018

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SummaryNovel therapies with unique new targets are needed for patients who are relapsed/refractory to current treatments for multiple myeloma. Ibrutinib is a first‐in‐class, once‐daily, oral covalent inhibitor of Bruton tyrosine kinase, which is overexpressed in the myeloma stem cell population. This study examined various doses of ibrutinib ± low‐dose dexamethasone in patients who received ≥2 prior lines of therapy, including an immunomodulatory agent. Daily ibrutinib ± weekly dexamethasone 40 mg was assessed in 4 cohorts using a Simon 2‐stage design. The primary objective was clinical benefit rate (CBR; ≥minimal response); secondary objectives included safety. Patients (n = 92) received a median of 4 prior regimens. Ibrutinib + dexamethasone produced the highest CBR (28%) in Cohort 4 (840 mg + dexamethasone; n = 43), with median duration of 9·2 months (range, 3·0–14·7). Progression‐free survival was 4·6 months (range, 0·4–17·3). Grade 3–4 haematological adverse events included anaemia (16%), thrombocytopenia (11%), and neutropenia (2%); grade 3–4 non‐haematological adverse events included pneumonia (7%), syncope (3%) and urinary tract infection (3%). Ibrutinib + dexamethasone produced notable responses in this heavily pre‐treated population. The encouraging efficacy, coupled with the favourable safety and tolerability profile of ibrutinib, supports its further evaluation as part of combination treatment.

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Section: Discussionmentioning

confidence: 99%

Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results

et al. 2018

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“…Many of the pro-tumorigenic effects of heparanase in myeloma have been shown to rely upon increased expression and shedding of syndecan-1 (Ramani et al, 2013). This proteoglycan is expressed on most myeloma tumor cells and is a critical determinant of myeloma cell survival and growth (Beauvais et al, 2016). Heparanase enhances syndecan-1 shedding by up-regulating the expression of matrix metalloproteinase 9 (MMP9) and urokinase plasminogen activator (uPA) that are recognized as syndecan sheddases (Purushothaman et al, 2008; Ramani et al, 2016).…”

Section: Heparanase and The Tumor Microenvironmentmentioning

confidence: 99%

Heparanase: From basic research to therapeutic applications in cancer and inflammation

Vlodavsky¹,

Singh²,

Boyango³

et al. 2016

Drug Resistance Updates

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Heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Heparanase expression is enhanced in almost all cancers examined including various carcinomas, sarcomas and hematological malignancies. Numerous clinical association studies have consistently demonstrated that upregulation of heparanase expression correlates with increased tumor size, tumor angiogenesis, enhanced metastasis and poor prognosis. In contrast, knockdown of heparanase or treatments of tumor-bearing mice with heparanase-inhibiting compounds, markedly attenuate tumor progression further underscoring the potential of anti-heparanase therapy for multiple types of cancer. Heparanase neutralizing monoclonal antibodies block myeloma and lymphoma tumor growth and dissemination; this is attributable to a combined effect on the tumor cells and/or cells of the tumor microenvironment. In fact, much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth, metastasis and chemoresistance. The repertoire of the physiopathological activities of heparanase is expanding. Specifically, heparanase regulates gene expression, activates cells of the innate immune system, promotes the formation of exosomes and autophagosomes, and stimulates signal transduction pathways via enzymatic and non-enzymatic activities. These effects dynamically impact multiple regulatory pathways that together drive inflammatory responses, tumor survival, growth, dissemination and drug resistance; but in the same time, may fulfill some normal functions associated, for example, with vesicular traffic, lysosomal-based secretion, stress response, and heparan sulfate turnover. Heparanase is upregulated in response to chemotherapy in cancer patients and the surviving cells acquire chemoresistance, attributed, at least in part, to autophagy. Consequently, heparanase inhibitors used in tandem with chemotherapeutic drugs overcome initial chemoresistance, providing a strong rationale for applying anti-heparanase therapy in combination with conventional anti-cancer drugs. Heparin-like compounds that inhibit heparanase activity are being evaluated in clinical trials for various types of cancer. Heparanase neutralizing monoclonal antibodies are being evaluated in pre-clinical studies, and heparanase-inhibiting small molecules are being developed based on the recently resolved crystal structure of the heparanase protein. Collectively, the emerging premise is that heparanase expressed by tumor cells, innate immune cells, activated endothelial cells as well as other cells of the tumor microenvironment is a master regulator of the aggressive phenotype of cancer, an important contributor to the poor outcome of cancer patients and a prime target for therapy.

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“…As is the case here, the interactions are extracellular and accessible to synthesized peptides that mimic the capture site in the syndecan. These peptides are called ‘synstatins’ or ‘SSTNs’ and act to competitively disrupt the signaling mechanism . In the case of VEGFR2 coupling to VLA‐4, peptides based on either the VEGFR2 docking site (SSTN VEGFR2 ) or the VLA‐4 docking site (SSTN VLA‐4 ) in syndecan‐1 serve to prevent tumor cell invasion or endothelial tube formation (Fig.…”

Section: A Novel Heparanase‐driven Mechanism Promoting Both Metastasimentioning

confidence: 99%

Heparanase regulation of cancer, autophagy and inflammation: new mechanisms and targets for therapy

et al. 2016

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Because of its impact on multiple biological pathways, heparanase has emerged as a major regulator of cancer, inflammation and other disease processes. Heparanase accomplishes this by degrading heparan sulfate which regulates the abundance and location of heparin-binding growth factors thereby influencing multiple signaling pathways that control gene expression, syndecan shedding and cell behavior. In addition, heparanase can act via non-enzymatic mechanisms that directly activate signaling at the cell surface. Clinical trials testing heparanase inhibitors as anti-cancer therapeutics are showing early signs of efficacy in patients further emphasizing the biological importance of this enzyme. This review focuses on recent developments in the field of heparanase regulation of cancer and inflammation, including the impact of heparanase on exosomes and autophagy, and novel mechanisms whereby heparanase regulates tumor metastasis, angiogenesis and chemoresistance. In addition, the ongoing development of heparanase inhibitors and their potential for treating cancer and inflammation are discussed.

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Syndecan-1 (CD138) Suppresses Apoptosis in Multiple Myeloma by Activating IGF1 Receptor: Prevention by SynstatinIGF1R Inhibits Tumor Growth

Cited by 55 publications

References 57 publications

Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results

Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results

Heparanase: From basic research to therapeutic applications in cancer and inflammation

Heparanase regulation of cancer, autophagy and inflammation: new mechanisms and targets for therapy

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