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Pancreatic ductal adenocarcinoma (PDAC) patients have poor prognosis and poor response to treatment. This is largely due to PDAC being associated with a dense and active stroma and tumor fibrosis (desmoplasia). Desmoplasia is characterized by excessive degradation and formation of the extracellular matrix (ECM) generating collagen fragments that are released into circulation. We evaluated the association of specific collagen fragments measured in pre-treatment serum with outcome in patients with PDAC. Matrix metalloprotease (MMP)-degraded type I collagen (C1M), type III collagen (C3M), type IV collagen (C4M) and a pro-peptide of type III collagen (PRO-C3) were measured by ELISA in pre-treatment serum from a randomized phase 3 clinical trial of patients with stage III/IV PDAC treated with 5-fluorouracil based therapy (n = 176). The collagen fragments were evaluated for their correlation (r, Spearman) with serum CA19-9 and for their association with overall survival (OS) based on Cox-regression analyses. In this phase 3 PDAC trial, pre-treatment serum collagen fragment levels were above the reference range for 67%-98% of patients, with median values in PDAC approximately two-fold higher than reference levels. Collagen fragment levels did not correlate with CA19-9 (r = 0.049–0.141, p = ns). On a continuous basis, higher levels of all collagen fragments were associated with significantly shorter OS. When evaluating degradation (C3M) and formation (PRO-C3) of type III collagen further, higher PRO-C3 was associated with poor OS (>25th percentile cut-point, HR = 2.01, 95%CI = 1.33–3.05) and higher C3M/PRO-C3 ratio was associated with improved OS (>25th percentile cut-point, HR = 0.53, 95%CI = 0.34–0.80). When adjusting for CA19–9 and clinical covariates, PRO-C3 remained significant (HR = 1.65, 95%CI = 1.09–2.48). In conclusion, collagen remodeling quantified in pre-treatment serum as a surrogate measure of desmoplasia was significantly associated with OS in a phase 3 clinical PDAC trial, supporting the link between desmoplasia, tumorigenesis, and response to treatment. If validated, these biomarkers may have prognostic and/or predictive potential in future PDAC trials.

Background and Aims: Hepatic fibrosis secondary to HCV infection can lead to cirrhosis and hepatic decompensation. Sustained virologic response (SVR) is possible with direct-acting antiviral drug regimens; however, patients with advanced fibrosis have an increased risk for HCC. Heat shock protein 47 (HSP47), a key collagen chaperone, has been implicated in fibrosis development. We evaluated the efficacy and safety of BMS-986263, a lipid nanoparticle delivering small interfering RNA designed to degrade HSP47 mRNA, for the treatment of advanced fibrosis.Approach and Results: NCT03420768 was a Phase 2, randomized (1:1:2), placebo-controlled trial conducted at a hepatology clinic in the United States.Patients with HCV-SVR (for ≥ 1 year) and advanced fibrosis received onceweekly i.v. infusions of placebo or BMS-986263 (45 or 90 mg) for 12 weeks.The primary endpoint was ≥ 1 METAVIR stage improvement at Week 12; key secondary endpoints included Ishak score improvement, pharmacokinetics, fibrosis biomarkers, and safety. All 61 patients completed treatment, and 2/15 (13%, placebo), 3/18 (17%, 45 mg), and 6/28 (21%, 90 mg) had METAVIR improvements of ≥ 1 stage at Week 12. Five patients in the 90-mg arm had Ishak improvements by ≥ 2 stages. BMS-986263 plasma concentrations increased in a generally dose-proportional fashion between BMS-986263 doses, with no notable accumulation with weekly dosing. All adverse events

Pycnodysostosis is an extremely rare genetic osteosclerosis caused by cathepsin K deficiency. We hypothesized that teriparatide, a potent anabolic agent used in the treatment of osteoporosis, might reduce skeletal fragility by activating bone turnover. We studied a typical case of pycnodysostosis in a 37-yr-old woman who exhibited short stature, skull and thorax deformities, and a history of severe fragility fractures. Cathepsin K gene sequencing was performed. Before and after 6 mo of 20 g/d teriparatide, biochemical markers of bone turnover were measured, and 3D bone structure and microarchitecture was assessed in vivo by HR-pQCT. Qualitative and quantitative analysis of transiliac bone biopsies were performed, and the degree of mineralization was evaluated by quantitative microradiography. In vitro assessment of bone resorption was performed after separation and differentiation of CD14 + monocytes from peripheral blood. Bone structure assessed by HR-pQCT on the radius and tibia showed augmentation of cortical and trabecular density. Transiliac bone biopsy showed highly increased bone mass (+63% versus age-and sex-matched controls), a decrease in bone remodeling without evidence of active osteoblasts, and a severe decrease in the dynamic parameters of bone formation (mineralizing surfaces, −90% and bone formation rate, −93% versus age-and sex-matched controls). This depressed bone turnover probably explained the increased degree of mineralization. The presence of a novel missense mutation leading to an A141V amino acid substitution confirmed a genetic defect of cathepsin K as the cause of the disease. The deficiency of active osteoclasts was confirmed by an in vitro study that showed a decreased concentration of CD14 + monocytes (the precursor of osteoclasts) in blood. These osteoclasts had low resorptive activity when incubated on bone slices. After 6 mo of teriparatide, the structure, microarchitecture, and turnover of bone-assessed by HR-pQCT, histology, and bone turnover markers-remained unchanged. Our data strongly suggest that some features of the osteoclastic phenotype-that are absent in pycnodysostosis-are a prerequisite for the anabolic effect of PTH on osteoblasts.