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Pacritinib to inhibit JAK/STAT signaling in refractory metastatic colon and rectal cancer.

ABSTRACT: Background: Treatment options for patients with refractory colorectal cancer are limited and typically provide a chance of only modest benefit. The goal of this study was to evaluate the benefit of inhibiting the JAK/STAT inflammatory pathway with single agent pacritinib in patients with metastatic refractory colorectal adenocarcinoma.

Methods: A single arm institutional trial was initiated and enrolled patients with metastatic colorectal cancer refractory to at least two standard lines of treatment. Pacritinib 400 mg daily was administered orally continuously in 28 day cycles.

Results: The trial was discontinued prior to reaching the planned accrual due to an FDA hold on pacritinib and a lack of treatment benefit. Eleven patients were enrolled and seven were evaluated for response. Median baseline C-reactive protein level was 12.1 (2.1-147) mg/L. One patient had stable disease at eight weeks by RECIST criteria and six progressed. There were no grade 4 or 5 adverse events while patients were on study. The grade 2 and lower AE events experienced were consistent with prior pacritinib trials.

Conclusions: In seven evaluable patients there were no objective responses. The trial was discontinued prior to completing planned accrual based on a low likelihood that the progression free survival goal of 4 months would be met.

SUBMITTER: Regenbogen T

PROVIDER: S-EPMC5750170 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Pacritinib to inhibit JAK/STAT signaling in refractory metastatic colon and rectal cancer.

Regenbogen Thomas T Chen Ling L Trinkaus Kathryn K Wang-Gillam Andrea A Tan Benjamin R BR Amin Manik M Pedersen Katrina S KS Park Haeseong H Suresh Rama R Lim Kian-Huat KH Ratchford Emily E Brown Amberly A Lockhart A Craig AC

Journal of gastrointestinal oncology 20171201 6

<h4>Background</h4>Treatment options for patients with refractory colorectal cancer are limited and typically provide a chance of only modest benefit. The goal of this study was to evaluate the benefit of inhibiting the JAK/STAT inflammatory pathway with single agent pacritinib in patients with metastatic refractory colorectal adenocarcinoma.<h4>Methods</h4>A single arm institutional trial was initiated and enrolled patients with metastatic colorectal cancer refractory to at least two standard l ...[more]

PMID: 29299358

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Project description:Background & aimsFunctional cure is achieved by a limited number of patients with chronic hepatitis B (CHB) after nucleotide analogue(s) and interferon treatment. It is urgent to develop therapies that can help a larger proportion of patients achieve functional cure. The present study was designed to explore the anti-hepatitis B virus (HBV) potency of interleukin-6 family cytokines and to characterize the underlying mechanisms of the cytokine displaying the highest anti-HBV potency.MethodsHBV-infected cells were used to screened the anti-HBV potency of interleukin-6 family cytokines. The concentration of oncostatin M (OSM) in patients with chronic HBV infection was examined by enzyme-linked immunosorbent assay. The underlying mechanism of OSM anti-HBV was explored through RNA-seq. C57BL/6 mice injected with rAAV8-1.3HBV were used to explore the suppression effect of OSM on HBV in vivo.ResultsOSM is the most effective of the interleukin-6 family cytokines for suppression of HBV replication (percentage of average inhibition: hepatitis B surface antigen, 34.44%; hepatitis B e antigen, 32.52%; HBV DNA, 61.57%). Hepatitis B e antigen-positive CHB patients with high OSM levels had lower hepatitis B surface antigen and hepatitis B e antigen than those with low levels. OSM activated JAK-STAT signaling pathway promoting the formation of STAT1-IRF9 transcription factor complex. Following this, OSM increased the expression of various genes with known functions in innate and adaptive immunity, which was higher expression in patients with CHB in immune clearance phase than in immune tolerance phase (data from GEO: GSE65359). Interferon-induced transmembrane protein 1, one of the most differentially expressed genes, was identified as an HBV restriction factor involved in OSM-mediated anti-HBV effect. In vivo, we also found OSM significantly inhibited HBV replication and induced expression of antiviral effector interferon-induced transmembrane protein 1.ConclusionsOur study shows that OSM remodels the immune response against HBV and exerts potent anti-HBV activity, supporting its further development as a potential therapy for treating CHB.

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Pacritinib to inhibit JAK/STAT signaling in refractory metastatic colon and rectal cancer.

Publications

Pacritinib to inhibit JAK/STAT signaling in refractory metastatic colon and rectal cancer.

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