Journal: Cancer Discovery

Article Title: Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRAS G12C

doi: 10.1158/2159-8290.CD-22-0158

Figure Lengend Snippet: JDQ443 displays antitumor activity across a range of cell-derived, KRAS G12C -dependent mouse tumor models, with efficacy driven by daily AUC. A, Aggregated best tumor growth inhibition in six KRAS G12C tumor models. JDQ443 efficacy was evaluated after oral dosing of 10, 30, and 100 mg/kg/day in six human KRAS G12C -mutant CDX models in mice. NSCLC cell line models are depicted in red, whereas PDAC (MIA Paca-2) and esophageal (KYSE410) cancer cell line models are shown in blue. Data are means from 2–11 independent in vivo studies. %Regr. is percentage tumor volume regression [–(Δtreated/treated at baseline) × 100], and %T/C is percentage tumor volume growth ratio [(Δtreated/Δcontrol) × 100]. B–G, CDX-bearing mice with KRAS G12C -mutated ( C–G ) and non–G12C-mutated (NCI-441, KRAS G12V ; B ) tumors were treated orally (p.o.) with JDQ443 at the indicated doses and schedules. G, LU99 tumor–bearing mice were treated with JDQ443 by continuous intravenous infusion using a programmable microinfusion pump. H and I, Simulated population-PK/PD metrics of daily AUC of JDQ443 in mouse blood ( H ) and average free KRAS G12C levels in tumor at steady state ( I ) are correlated with the observed efficacy in LU99 (%T/C or % regression). Points correspond to the mean and the error bars to ± 1 SD of the simulated PK/PD metrics based on 100 simulations and observed efficacy metrics. *, P < 0.05 versus vehicle; #, P < 0.05 versus each other, by one-way ANOVA.

Article Snippet: To assess the effect of continuous dosing on tumor growth, LU99 tumor–bearing nude mice were implanted subcutaneously with a programmable microinfusion pump (iPRECIO, SMP310R, Primetech Corporation) as previously described ( ).

Techniques: Activity Assay, Derivative Assay, Inhibition, Mutagenesis, In Vivo

Journal: Science translational medicine

Article Title: Miniaturized neural system for chronic, local intracerebral drug delivery

doi: 10.1126/scitranslmed.aan2742

Figure Lengend Snippet: (A) Image of a MiNDS with U-junctions connected to two independently controlled iPrecio SMP-300 pumps. (B) Illustration of in vitro pump characterization setup with distinct layers of water and oil in the weighing dish as represented in green dashed box. (C) Line graph showing the mean infusion profiles of three infusion trials through S-MiNDS with flow rates 0.1, 1, and 10 μl/hour. End infusion (E.I.) (black dashed line) represents the end of infusion, and total volume (T.V.) (colored dashed lines) denotes the theoretical value of the volume infused. (D) Positron emission tomography (PET) images of Cu-64 in vivo delivery via an implanted MiNDS as seen in (A) (3 μCi/μl iPrecio infusion, 1.67-μl infusion at 10 μl/hour). Representative images at 5, 10, 15, and 20 min after Cu-64 injection show Cu-64 expression (fluorescence scale is depicted on the right). (E) Normalized fluorescence intensity in relation to position across the bolus. The diameter (w) of the bolus was determined using a three-dimensional (3D) region of interest (ROI), where the borders were defined as 10% of peak core intensity (I). (F) Normalized ROI sum fluorescence intensity at different times for identical Cu-64 infusions delivered into an agarose phantom (0.6% by weight) and in the rat brain through implanted S-MiNDSs using a syringe pump and an iPrecio pump (n = 3 trials; error bars represent SE). Statistical analysis was done using one-way ANOVA followed by Tukey post hoc test at each time point. Significance differences were only found at time = 20 min. *P < 0.05. DI, deionized.

Article Snippet: For each of the two iPrecio SMP-300 pumps (Primetech Corp.) used, the original external tubing was cut, leaving only the first 2.5 mm of outlet tubing ( fig. S12, A and B ).

Techniques: In Vitro, Positron Emission Tomography, In Vivo, Injection, Expressing, Fluorescence