Gene expression profiles from plucked scalp hair to assess pharmacodynamic biomarkers following treatment of advanced solid tumors with a novel anti-cancer stem cell Wnt inhibitor

Wnt signaling pathway genes are crucial for cell fate determination and cell polarity during development. To date 19 Wnt ligands and 10 frizzled receptors have been characterized with many of these genes being implicated in tumor formation and progression. Strategies for anti-cancer intervention targeting these pathways are in development but due to complexity of Wnt signaling pathway regulation more research is needed to identify the most beneficial therapy to treat specific tumors.

Ipafricept (OMP-54F28) is a first in class recombinant fusion protein with the extracellular part of human Frizzled 8 receptor fused to a human IgG1 Fc fragment that binds Wnt ligands. This truncated decoy receptor binds to a cystine-rich region of Wnt ligand and as a result it blocks the activation of the Wnt signaling.

In this study the authors designed and executed a first-in-human Phase 1 clinical trial to evaluate dose-limiting toxicity, safety, pharmacokinetics (PK), preliminary efficacy and investigate the mechanism of action of a novel drug Ipafricept (OMP-54F28) in patients with solid tumors.

In the trial, the monoclonal antibody treatment was administered intravenously over period of 30 minutes every 3 weeks for 9 weeks in 7 dose-escalation cohorts in 26 patients with a range of advanced solid tumors, including lung, colorectal and pancreatic tumors.

Primary objectives were to determine dose limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives were pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity and antitumor activity.

Patients experienced some mild adverse effects related to the drug suggesting safety of drug at the doses tested. The drug did display unique toxicity in relation to bone remodeling with six patients showing reversible (upon administration of zoledronic acid) elevation of beta-CTX, a bone turnover marker and 2 subjects receiving the highest dose of the drug experienced fragility fractures.

PK of Ipafricept (OMP-54F28) was assessed by ELISA and appeared to be mostly linear in the dose ranges studied. The efficacious dose was estimated to be 10mg/kg and the drug half-life was about 4 days and no notable drug accumulation was observed suggesting a rapid drug turnover.

The anti-tumor activity of Ipafricept (OMP-54F28) was assessed following RECIST 1.1 solid tumor assessment criteria. Although no notable complete or partial responses were observed, seven patients remained in a stable disease (SD) condition while one subject remained free of disease progression for over 9 months post treatment. Whilst not conclusive, these observations were reported to be indicative of a biological effect.

To demonstrate target engagement as well as confirming the mechanism of action of the drug, pharmacodynamic biomarkers were evaluated using plucked scalp hair as a surrogate tissue. Plucked scalp hair was collected pre- and post-treatment and was harvested from trial subjects as well as healthy volunteers. RNA extracted from the bulb region of the plucked scalp hair samples were assessed by microarray analysis.

The results of the study showed a dose-dependent decrease in the expression of Wnt pathway genes in patients treated with Ipafricept (OMP-54F28). In addition, patients also showed an increased expression of cell differentiation genes.

Here the authors described the results of a phase 1 first-in-human clinical trial of a Wnt inhibitor designed as a decoy for Wnt signaling. The drug was tolerated well and achieved an efficacious dose. Gene expression analysis using plucked hair confirmed that the drug successfully inhibited Wnt pathways. There was, however, limited indication of an anti-tumor response across the panel of solid tumors examined. The authors concluded that more research was required to identify patients/cancers that may respond well to Ipafricept and suggested that Ipafricept could work well in combination with other therapeutic agents.

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Epistem's Hair Biomarker Platform and Cancer Stem Cell Assays

Epistem provides a unique plucked hair biomarker platform for targeting intracellular signaling pathways in oncology, inflammation, fibrosis and other therapeutic areas. Plucked hair provides a minimally invasive surrogate tissue to assess epithelial tissue drug-induced changes. Effects on mRNA and protein expression levels can be analyzed. Epistem is able to establish ideal biomarker to target in clinical settings using a range of preclinical models which include assessing human plucked scalp hair ex vivo in the presence of compounds at different concentrations. Epistem's histology and gene expression services are GCLP-compliant, and we have participated in and supported many clinical studies. We have in-house bioinformatics support for all of our gene expression studies and have extensive experience identifying biomarkers or biomarker signatures in a variety of tissues.

We offer a cancer stem cell assay, based on the sphere forming capabilities of stem cell that can be used to screen anti-cancer therapeutics. We have also adapted this model as an add-on to our in vivo xenograft and orthotopic models, where any remaining tumor tissue can be excised and assayed for sphere forming ability post drug treatment.

Jimeno et al., A first-in-human Phase 1 study of the anti-cancer stem cell agent Ipafricept (OMP-54F28) a decoy for Wnt ligands, in patients with advanced solid tumors, Clinical Cancer Research, 2017 December 15; 23(24):7490-7497. doi: 10.1158/1078-0432.CCR-17-2157

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