Pacritinib protects dendritic cells more efficiently than ruxolitinib

Heine, Annkristin; Wolf, Anna Maria; Schlaweck, Sebastian; Daecke, Solveig Nora; Brossart, Peter; Wolf, Dominik

doi:10.1016/j.exphem.2021.06.004

Cited by 3 publications

(2 citation statements)

References 11 publications

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“…Pacritinib is approved for myelofibrosis and inhibits IRAK1 and downstream activation from TLR4, though pediatric studies have not yet been completed. Ruxolitinib, on the other hand, has approval for pediatric graft vs. host disease and provides downstream inhibition of TLR signaling [ 35 ]. Emavusertib is in clinical trials for lymphoma and leukemia and crosses the blood–brain barrier.…”

Section: Discussionmentioning

confidence: 99%

Femoral Structure and Biomechanical Characteristics in Sanfilippo Syndrome Type-B Mice

Ashby,

Castillo,

Ludwig

et al. 2023

IJMS

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Sanfilippo syndrome Type-B, also known as mucopolysaccharidosis IIIB (MPS IIIB), accounts for approximately one-third of all Sanfilippo syndrome patients and is characterized by a similar natural history as Type-A. Patients suffer from developmental regression, bone malformation, organomegaly, GI distress, and profound neurological deficits. Despite human trials of enzyme replacement therapy (ERT) (SBC-103, AX250) in MPS IIIB, there is currently no FDA approved treatment and a few palliative options. The major concerns of ERT and gene therapy for the treatment of bone malformation are the inadequate biodistribution of the missing enzyme, N-acetyl-α-glucosaminidase (NAGLU), and that the skeleton is a poorly hit target tissue in ERT and gene therapy. Each of the four known human types of MPS III (A, B, C, and D) is usually regarded as having mild bone manifestations, yet it remains poorly characterized. This study aimed to determine bone mineral content (BMC), volumetric bone mineral density (vBMD), and biomechanical properties in femurs MPS IIIB C57BL/6 mice compared to phenotypic control C57BL/6 mice. Significant differences were observed in MPS IIIB mice within various cortical and cancellous bone parameters for both males and females (p < 0.05). Here, we establish some osteogenic manifestations of MPS IIIB within the mouse model by radiographic and biomechanical tests, which are also differentially affected by age and sex. This suggests that some skeletal features of the MPS IIIB mouse model may be used as biomarkers of peripheral disease correction for preclinical treatment of MPS IIIB.

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Section: Discussionmentioning

confidence: 99%

Femoral Structure and Biomechanical Characteristics in Sanfilippo Syndrome Type-B Mice

Ashby,

Castillo,

Ludwig

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…As a note of caution when considering combination approaches, the JAK-inhibitor ruxolitinib has been shown to impair DC cell function both in vitro and in vivo [ 202 ]. To overcome this issue, the same team has identified a different JAK inhibitor, pacritinib, that can effectively conserve DC function when compared to ruxolitinib [ 203 ].…”

Section: Signaling Pathways Modulators and Combinations With Ovs For ...mentioning

confidence: 99%

Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways

et al. 2022

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Oncolytic viruses (OVs) represent a new class of multi-modal immunotherapies for cancer, with OV-elicited antitumor immunity being key to their overall therapeutic efficacy. Currently, the clinical effectiveness of OV as monotherapy remains limited, and thus investigators have been exploring various combinations with other anti-cancer agents and demonstrated improved therapeutic efficacy. As cancer cells have evolved to alter key signaling pathways for enhanced cell proliferation, cancer progression and metastasis, these cellular and molecular changes offer promising targets for rational cancer therapy design. In this regard, key molecules in relevant signaling pathways for cancer cells or/and immune cells, such as EGFR-KRAS (e.g., KRASG12C), PI3K-AKT-mTOR, ERK-MEK, JAK-STAT, p53, PD-1-PD-L1, and epigenetic, or immune pathways (e.g., histone deacetylases, cGAS-STING) are currently under investigation and have the potential to synergize with OV to modulate the immune milieu of the tumor microenvironment (TME), thereby improving and sustaining antitumor immunity. As many small molecule modulators of these signaling pathways have been developed and have shown strong therapeutic potential, here we review key findings related to both OV-mediated immunotherapy and the utility of small molecule modulators of signaling pathways in immuno-oncology. Then, we focus on discussion of the rationales and potential strategies for combining OV with selected modulators targeting key cellular signaling pathways in cancer or/and immune cells to modulate the TME and enhance antitumor immunity and therapeutic efficacy. Finally, we provide perspectives and viewpoints on the application of novel experimental systems and technologies that can propel this exciting branch of medicine into a bright future.

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Immune Dysregulation and Infectious Complications in MPN Patients Treated With JAK Inhibitors

Cattaneo

Iurlo

2021

Front. Immunol.

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BCR-ABL1-negative myeloproliferative neoplasms are burdened by a reduced life expectancy mostly due to an increased risk of thrombo-hemorrhagic events, fibrotic progression/leukemic evolution, and infectious complications. In these clonal myeloid malignancies, JAK2V617F is the main driver mutation, leading to an aberrant activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. Therefore, its inhibition represents an attractive therapeutic strategy for these disorders. Several JAK inhibitors have entered clinical trials, including ruxolitinib, the first JAK1/2 inhibitor to become commercially available for the treatment of myelofibrosis and polycythemia vera. Due to interference with the JAK-STAT pathway, JAK inhibitors affect several components of the innate and adaptive immune systems such as dendritic cells, natural killer cells, T helper cells, and regulatory T cells. Therefore, even though the clinical use of these drugs in MPN patients has led to a dramatic improvement of symptoms control, organ involvement, and quality of life, JAK inhibitors–related loss of function in JAK-STAT signaling pathway can be a cause of different adverse events, including those related to a condition of immune suppression or deficiency. This review article will provide a comprehensive overview of the current knowledge on JAK inhibitors’ effects on immune cells as well as their clinical consequences, particularly with regards to infectious complications.

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Pacritinib protects dendritic cells more efficiently than ruxolitinib

Cited by 3 publications

References 11 publications

Femoral Structure and Biomechanical Characteristics in Sanfilippo Syndrome Type-B Mice

Femoral Structure and Biomechanical Characteristics in Sanfilippo Syndrome Type-B Mice

Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways

Immune Dysregulation and Infectious Complications in MPN Patients Treated With JAK Inhibitors

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