GPCR antagonist (Hope Medicine)

Sonic hedgehog (SHH), an activating ligand of smoothened (SMO), is overexpressed in > 70% of pancreatic cancers (PCs). We investigated the impact of vismodegib, an SHH antagonist, plus gemcitabine (GV) or gemcitabine plus placebo (GP) in a multicenter phase Ib/randomized phase II trial and preclinical PC models.

Patients with PC not amenable to curative therapy who had received no prior therapy for metastatic disease and had Karnofsky performance score ≥ 80 were enrolled. Patients were randomly assigned in a one-to-one ratio to GV or GP. The primary end point was progression-free-survival (PFS). Exploratory correlative studies included serial SHH serum levels and contrast perfusion computed tomography imaging. To further investigate putative biologic mechanisms of SMO inhibition, two autochthonous pancreatic cancer models (KrasG12D; p16/p19fl/fl; Pdx1-Cre and KrasG12D; p53R270H/wt; Pdx1-Cre) were studied.

No safety issues were identified in the phase Ib portion (n = 7), and the phase II study enrolled 106 evaluable patients (n = 53 in each arm). Median PFS was 4.0 and 2.5 months for GV and GP arms, respectively (95% CI, 2.5 to 5.3 and 1.9 to 3.8, respectively; adjusted hazard ratio, 0.81; 95% CI, 0.54 to 1.21; P = .30). Median overall survival (OS) was 6.9 and 6.1 months for GV and GP arms, respectively (95% CI, 5.8 to 8.0 and 5.0 to 8.0, respectively; adjusted hazard ratio, 1.04; 95% CI, 0.69 to 1.58; P = .84). Response rates were not significantly different. There were no significant associations between correlative markers and overall response rate, PFS, or OS. Preclinical trials revealed no significant differences with vismodegib in drug delivery, tumor growth rate, or OS in either model.

The addition of vismodegib to gemcitabine in an unselected cohort did not improve overall response rate, PFS, or OS in patients with metastatic PC. Our preclinical and clinical results revealed no statistically significant differences with respect to drug delivery or treatment efficacy using vismodegib.

We have demonstrated decreased microvascular sensitivity to norepinephrine during endotoxin shock possibly related to reduced sympathetic receptor activity (Baker et al.: Circ Shock 12:165-176, 1984). The response to other vascular controls such as arginine vasopressin (AVP) may also be altered. Reactivity of the left cremaster muscle microvessels of pentobarbital anesthetized Wistar rats was studied using videomicroscopy and videodensitometry. Femoral arterial pressure (Pm), dose response curves of vessel diameters to topical arginine vasopressin (10(-15) to 10(-6) M), FITC-albumin mean transit times, and plasma velocities were obtained. Escherichia coli endotoxin (6 mg/kg i.v., LD100) was infused over a 1-hr period. Parameter measurements were repeated at 30 min and 90 min post-endotoxin. Both Pm and plasma velocities progressively decreased. Arteriolar constriction and the mean transit times of FITC-labeled albumin progressively increased. The threshold dose for AVP averaged 10(-9) M at control and decreased to 10(-14) M post-endotoxin. Venular diameters were not altered by AVP. The AVP antagonist did not alter the microvascular diameter response to endotoxin but did block the responses to topical and endogenous AVP since arterial pressure and flow velocity decreased at a significantly greater rate than in rats without antagonist. Plasma AVP levels were significantly increased by endotoxin. Reduced alpha adrenergic sensitivity may unmask the responsiveness to AVP or increase the sensitivity of AVP receptors. Increased endogenous AVP may require a smaller exogenous concentration of AVP for constriction.