Targeting the Wnt signaling pathway for the development of novel therapies for osteoporosis

Yavropoulou, Maria P; Papapoulos, Socrates E.

doi:10.1586/eem.10.48

Cited by 5 publications

(3 citation statements)

References 109 publications

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“…In comparison, less than 19% of the intratumorally injected free 3 H-R848 could be detected in the tumor after 30 minutes, and less than 1% were found at all time points in intravenously injected mice. This observation is comparable to previous reports on intratumoral drug retention of small molecules and underlines the importance of a depot technology to achieve the essential sustained stimulation [33][34][35] . Mice injected with CarboCell TLR also displayed much lower 3 H-R848 organ activity compared to mice injected with free intratumoral and intravenous 3 H-R848 (Fig.…”

Section: Carbocell Provides Sustained Tumor Drug Activity and Minimal...supporting

confidence: 89%

CarboCell combinatorial immunotherapy orchestrates curative anticancer immune activation of the tumor microenvironment

Jensen

Serrano-Chávez

Halldórsdóttir

et al. 2023

Preprint

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Cancer curing immune responses against heterogeneous solid cancers require that a coordinated immune activation is initiated in the antigen avid but immunosuppressive tumor microenvironment (TME). The plastic, immunosuppressive TME, and the poor systemic tolerability of immune activating drugs are, however, fundamental barriers to generating curative anticancer immune responses. Here, we introduce the CarboCell technology to overcome these barriers by forming a sustained drug release depot at the injection site that provides high payloads of immune stimulatory drugs selectively within the TME. The CarboCell thereby induces a hot spot for immune cell training and polarization and further drives and maintains the tumor-draining lymph nodes in an anticancer and immune activated state. Mechanistically, this transforms cancerous tissues to allow infiltration of T cells, consequently generating systemic anticancer immunoreactivity. The CarboCell technology can release multiple small molecule drugs - each with tailored release profiles - rendering it active across the broad composition of TME backgrounds. In the current study, impressive therapeutic performance is presented for a dual-drug CarboCell providing sustained release of a Toll-like receptor 7/8 agonist and a transforming growth factor-β inhibitor. CarboCell can be injected through standard clinical thin-needle technologies. Its inherent magnetic resonance imaging and ultrasound visibility, and optional radiographic contrast, make it possible to validate and plan CarboCell injections across clinical imaging modalities. These features, in combination with attractive injection intervals, secure optimal patient compliance and open new possibilities for intratumoral immunotherapy accurately across basically all anatomical locations.

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Section: Carbocell Provides Sustained Tumor Drug Activity and Minimal...supporting

confidence: 89%

CarboCell combinatorial immunotherapy orchestrates curative anticancer immune activation of the tumor microenvironment

Jensen

Serrano-Chávez

Halldórsdóttir

et al. 2023

Preprint

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“…Human and animal genetics have indicated that this may be feasible. In particular, the recognition of the pivotal role of Wnt signalling pathway in bone formation provided a number of potential targets for the development of new pharmaceuticals 12. For clinical use, however, treatments should modify the expression of target molecules but also need to have bone specificity to avoid potential effects on other organs in the body.…”

Section: Sclerostin Expression and Mechanism Of Actionmentioning

confidence: 99%

Targeting sclerostin as potential treatment of osteoporosis

Papapoulos

2011

Annals of the Rheumatic Diseases

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In recent years, study of rare bone diseases has led to the identification of signalling pathways that regulate bone formation and provided targets for the development of novel therapeutic agents to stimulate bone formation in patients with osteoporosis. Studies of two bone sclerosing dysplasias, sclerosteosis and van Buchem disease led to the identification of sclerostin, a negative regulator of bone formation. Sclerostin binds to LRP5/6 and inhibits Wnt signalling, but its precise molecular mechanism of action is not yet known. Its expression is restricted in the skeleton to osteocytes and is modified by mechanical loading and parathyroid hormone treatment. Sclerostin deficiency reproduces the findings of the human diseases in mice, while sclerostin excess leads to bone loss and reduced bone strength. An antibody to sclerostin increased bone formation dramatically at all bone envelopes in ovariectomised rats and intact monkeys, without affecting bone resorption and improved bone strength. In initial human studies, a single injection of the antibody to postmenopausal women increased serum P1NP and transiently decreased serum CTX. Clinical phase II studies with this antibody are currently underway.

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“…Advanced age and female sex are the most important risk factors for osteoporosis (Kling, Clarke, & Sandhu, ). Most of the current treatments for osteoporosis work by repressing osteoclast activity and slowing bone resorption (Yavropoulou & Papapoulos, ). However, the long‐term inhibition of bone resorption appears to be ineffective in bone remolding (Hasan, ).…”

Section: Introductionmentioning

confidence: 99%

Anti‐osteoporosis activity of Sanguinarine in preosteoblast MC3T3‐E1 cells and an ovariectomized rat model

Fuzhan

Xie

Wang

et al. 2018

Journal Cellular Physiology

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Sanguinarine, a benzophenanthridine alkaloid, has been previously demonstrated to exert antimicrobial, anti-inflammatory, and anti-tumor activities. A previous study has identified Sanguinarine as a potential drug candidate for osteoporosis treatment by computational bioinformatics analysis. This study further evaluated the effects of Sanguinarine on the differentiation of murine preosteoblast MC3T3-E1 cells and its anti-osteoporosis activity in an ovarietomized rat model. Sanguinarine treatment (0.25, 0.5, 1, and 2 µm) of MC3T3-E1 cells significantly increased alkaline phosphatase (ALP) activity and the phoshporalyation of AMP-activated protein kinase α subunit (AMPKα), but did not affect cell proliferation. The induction effects of Sanguinarine treatment (2 µm) on ALP activity, AMPKα phosphorylation, Smad1 phosphorylation, and the expression of three osteoblast differentiation-regulators (bone morphogenetic protein 2 [BMP2], osterix [OSX], and osteoprotegerin [OPG]) were partially reversed by Compound C treatment. More importantly, Sanguinarine treatment promoted bone tissue growth in an ovariectomized (OVX) osteoporosis rat model as evaluated by histological examination, micro-CT analysis, and serum parameter detection. In conclusion, these results indicate that Sanguinarine induces the differentiation of MC3T3-E1 cells through the activation of the AMPK/Smad1 signaling pathway. Sanguinarine can stimulate bone growth in vivo and may be an effective drug for osteoporosis treatment.

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Targeting the Wnt signaling pathway for the development of novel therapies for osteoporosis

Cited by 5 publications

References 109 publications

CarboCell combinatorial immunotherapy orchestrates curative anticancer immune activation of the tumor microenvironment

CarboCell combinatorial immunotherapy orchestrates curative anticancer immune activation of the tumor microenvironment

Targeting sclerostin as potential treatment of osteoporosis

Anti‐osteoporosis activity of Sanguinarine in preosteoblast MC3T3‐E1 cells and an ovariectomized rat model

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