ABSTRACT
Fibroblast growth factor receptor (FGFR) kinase inhibitors have been shown to be effective in the treatment of intrahepatic cholangiocarcinoma and other advanced solid tumors harboring FGFR2 alterations, but the toxicity of these drugs frequently leads to dose reduction or interruption of treatment such that maximum efficacy cannot be achieved. The most common adverse effects are hyperphosphatemia caused by FGFR1 inhibition and diarrhea due to FGFR4 inhibition, as current therapies are not selective among the FGFRs. Designing selective inhibitors has proved difficult with conventional approaches because the orthosteric sites of FGFR family members are observed to be highly similar in X-ray structures. In this study, aided by analysis of protein dynamics, we designed a selective, covalent FGFR2 inhibitor. In a key initial step, analysis of long-timescale molecular dynamics simulations of the FGFR1 and FGFR2 kinase domains allowed us to identify differential motion in their P-loops, which are located adjacent to the orthosteric site. Using this insight, we were able to design orthosteric binders that selectively and covalently engage the P-loop of FGFR2. Our drug discovery efforts culminated in the development of lirafugratinib (RLY-4008), a covalent inhibitor of FGFR2 that shows substantial selectivity over FGFR1 (~250-fold) and FGFR4 (~5,000-fold) in vitro, causes tumor regression in multiple FGFR2-altered human xenograft models, and was recently demonstrated to be efficacious in the clinic at doses that do not induce clinically significant hyperphosphatemia or diarrhea.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Hyperphosphatemia , Humans , Receptor, Fibroblast Growth Factor, Type 2/genetics , Receptor, Fibroblast Growth Factor, Type 2/chemistry , Bile Ducts, Intrahepatic/metabolism , Diarrhea , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistryABSTRACT
Oncogenic activation of fibroblast growth factor receptor 2 (FGFR2) drives multiple cancers and represents a broad therapeutic opportunity, yet selective targeting of FGFR2 has not been achieved. Although the clinical efficacy of pan-FGFR inhibitors (pan-FGFRi) validates FGFR2 driver status in FGFR2 fusion-positive intrahepatic cholangiocarcinoma, their benefit is limited by incomplete target coverage due to FGFR1- and FGFR4-mediated toxicities (hyperphosphatemia and diarrhea, respectively) and the emergence of FGFR2 resistance mutations. RLY-4008 is a highly selective, irreversible FGFR2 inhibitor designed to overcome these limitations. In vitro, RLY-4008 demonstrates >250- and >5,000-fold selectivity over FGFR1 and FGFR4, respectively, and targets primary alterations and resistance mutations. In vivo, RLY-4008 induces regression in multiple xenograft models-including models with FGFR2 resistance mutations that drive clinical progression on current pan-FGFRi-while sparing FGFR1 and FGFR4. In early clinical testing, RLY-4008 induced responses without clinically significant off-isoform FGFR toxicities, confirming the broad therapeutic potential of selective FGFR2 targeting. SIGNIFICANCE: Patients with FGFR2-driven cancers derive limited benefit from pan-FGFRi due to multiple FGFR1-4-mediated toxicities and acquired FGFR2 resistance mutations. RLY-4008 is a highly selective FGFR2 inhibitor that targets primary alterations and resistance mutations and induces tumor regression while sparing other FGFRs, suggesting it may have broad therapeutic potential. See related commentary by Tripathi et al., p. 1964. This article is featured in Selected Articles from This Issue, p. 1949.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Humans , Receptor, Fibroblast Growth Factor, Type 2/genetics , Mutation , Cholangiocarcinoma/genetics , Bile Duct Neoplasms/drug therapy , Bile Ducts, Intrahepatic/metabolism , Protein Kinase Inhibitors/therapeutic useABSTRACT
Early spatial skills predict the development of later spatial and mathematical skills. Yet, it is unclear how comprehension of the words that capture spatial relations, words like behind and under, might be associated with children's early spatial and mathematics skills. The current study addressed this question by conducting a moderated mediation model to test the potential moderating effects of group factors, such as socioeconomic status (SES) and gender, on the possible mediation of spatial language comprehension on the association between spatial skill and mathematics performance. In total, 192 3-year-olds were tested on a battery of assessments, including a novel Spatial Language Comprehension Task, a test of spatial skills (2- and 3-dimensional trials of the Test of Spatial Assembly [2D and 3D TOSA, respectively]), and a composite of 2 mathematical assessments. The results indicate that this novel Spatial Language Comprehension Task is a reliable measure useful for examining group differences and the early space-math link. Specifically, higher-SES preschoolers and females had higher spatial language comprehension compared with their lower-SES peers and males, respectively. These SES and gender disparities in spatial language comprehension are concerning, given the strong association between spatial language comprehension and mathematics skills. Additionally, spatial language comprehension mediated the association between spatial skill and mathematics performance for females only. Future work should examine the potential causal role that spatial language comprehension may have in concurrent and later spatial and mathematics skills. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Subject(s)
Comprehension , Social Class , Child , Child, Preschool , Female , Humans , Male , MathematicsABSTRACT
Spatial skills are associated with mathematics skills, but it is unclear if spatial training transfers to mathematics skills for preschoolers, especially from underserved communities. The current study tested (a) whether spatial training benefited preschoolers' spatial and mathematics skills, (b) if the type of feedback provided during spatial training differentially influenced children's spatial and mathematics skills, and (c) if the spatial training's effects varied by socioeconomic status (SES). Preschoolers (N = 187) were randomly assigned to either a 'business-as-usual' control or one of three spatial training groups (modeling and feedback [MF]; gesture feedback [GF]; spatial language feedback [SLF]). Three-year-olds were trained to construct puzzles to match a model composed of various geometric shapes. New models were created similar to the 2-dimensional trials of the Test of Spatial Assembly (TOSA). Training was given once per week for 5 weeks. Preschoolers were pretested and posttested on 2D and 3D TOSA trials, spatial vocabulary, shape identification, and 2 mathematics assessments. Results indicate that first, any spatial training improved preschoolers' 2D TOSA performance, although a significant interaction with SES indicated improvement was driven by low-SES children. Furthermore, low-SES children showed greatest gains on the 2D TOSA with MF and GF. Second, MF and GF improved low-SES children's performance on the 3D TOSA. Third, only low-SES children with MF saw improvements in far-transfer to mathematics (Woodcock-Johnson: Applied Problems, but not the Test of Early Mathematical Ability). Results indicate that, especially for low-income learners, spatial training can improve children's early spatial and mathematics skills. (PsycINFO Database Record (c) 2020 APA, all rights reserved).
Subject(s)
Early Intervention, Educational , Feedback, Physiological/physiology , Gestures , Mathematical Concepts , Mathematics/education , Psychomotor Performance/physiology , Social Class , Space Perception/physiology , Transfer, Psychology/physiology , Vocabulary , Child, Preschool , Female , Humans , MaleABSTRACT
Geometric forms have formal definitions. While knowing shape names is considered important for school-readiness, many children do not understand the defining features of shapes until well into elementary school (Satlow & Newcombe, 1998). One reason is likely that they do not encounter enough variety in the shapes they see (citation removed). The present study observed 60 parents and their 3-year-old children during play with geometric toys, exploring how spatial language varied with the nature of the shape-toy set (canonical shapes versus a mix of canonical and unusual or less-canonical variants) and whether geometric shapes were presented as tangible, traditional toys or shown on a touchscreen tablet app. Although children in the app condition heard more shape names than the other conditions due to the language produced by the app itself, children used more overall words and more spatial language with tangible toys that included varied shapes. In addition, parents used more shape names with sons than with daughters and tended to adjust their use of spatial language more in response to varied shape sets with boys, although these findings need replication to evaluate generality. These data suggest that including non-canonical shapes in tangible shape toys may provide a low-cost, high-impact way of refining adult-child interactions that might facilitate children's early geometric knowledge.