Selective FGFR/FGF pathway inhibitors: inhibition strategies, clinical activities, resistance mutations, and future directions

Expert review of clinical pharmacology

2021 Oct 01

Repetto, M;Crimini, E;Giugliano, F;Morganti, S;Belli, C;Curigliano, G;
PMID: 34591728 | DOI: 10.1080/17512433.2021.1947246

Introduction: Fibroblast growth factor receptor (FGFR)/fibroblast growth factor (FGF) is a pathway characterized by recurring alterations in cancer. Its dysregulations enhance cancer cell proliferation, survival, migration and invasion, as well as angiogenesis and immune evasion.Areas covered: FGFR/FGF selective inhibitors belong to a broad class of drugs with some being approved for specific indications and others under investigation in ongoing phase I and II clinical trials. In this review, all available clinical data from trials on selective FGFR/FGF inhibitors as well as described resistance mutations and mechanisms are presented. FGFR/FGF pathway inhibitors are classified according to the mechanism they employ to dampen/suppress signaling and to the preferred FGFR binding mode when X-ray crystal structure is available.Expert opinion: Data presented suggests the general actionability of FGFR1,2,3 mutations and fusions across histologies, whereas FGFR1,2,3 amplifications alone are poor predictors of response to tyrosine kinase inhibitors. Overexpression on immunohistochemistry (IHC) of FGF19, the stimulatory ligand of FGFR4, can predict response to FGFR selective inhibitors in hepatocellular carcinoma. Whereas IHC overexpression of FGFR1,2,3 is not sufficient to predict benefit from FGFR inhibitors across solid tumors. FGFR1,2,3 mRNA overexpression can predict response even in absence of structural alteration. Data on resistance mutations suggests the need for new inhibitors to overcome gatekeeper mutations.

Norrie disease protein is essential for cochlear hair cell maturation

Proceedings of the National Academy of Sciences of the United States of America

2021 Sep 28

Hayashi, Y;Chiang, H;Tian, C;Indzhykulian, AA;Edge, ASB;
PMID: 34544869 | DOI: 10.1073/pnas.2106369118

Mutations in the gene for Norrie disease protein (Ndp) cause syndromic deafness and blindness. We show here that cochlear function in an Ndp knockout mouse deteriorated with age: At P3-P4, hair cells (HCs) showed progressive loss of Pou4f3 and Gfi1, key transcription factors for HC maturation, and Myo7a, a specialized myosin required for normal function of HC stereocilia. Loss of expression of these genes correlated to increasing HC loss and profound hearing loss by 2 mo. We show that overexpression of the Ndp gene in neonatal supporting cells or, remarkably, up-regulation of canonical Wnt signaling in HCs rescued HCs and cochlear function. We conclude that Ndp secreted from supporting cells orchestrates a transcriptional network for the maintenance and survival of HCs and that increasing the level of β-catenin, the intracellular effector of Wnt signaling, is sufficient to replace the functional requirement for Ndp in the cochlea.

CONSEQUENCES OF mTOR INHIBITION ON AAV HEPATIC TRANSDUCTION EFFICACY

Human gene therapy

2021 Sep 24

Perez-Iturralde, A;Carte, B;Aldabe, R;
PMID: 34555962 | DOI: 10.1089/hum.2021.171

The efficiency of recombinant Adeno-associated virus vectors (AAV) transducing host cells is very low, limiting their therapeutic potential in patients. There are several cellular pathways interacting and interfering with the journey of the AAV from the cell surface to the nucleus, opening the possibility to enhance AAV transduction by modifying these interactions. In this study, we explored the results of AAV hepatic transduction when different mTOR inhibitors.- rapamycin, MLN0128, RapaLink-1 -were used in preconditioned juvenile and adult mice. We confirmed rapamycin as an AAV hepatic transduction enhancer in juvenile and adult mice; however, RapaLink-1, a stronger mTOR inhibitor and a clear hepatic autophagy inducer, had no positive effect. Moreover, MLN0128 reduced AAV hepatic transduction. Therefore, our results show a complex interaction between the mTOR pathway and AAV-mediated hepatic transduction and indicate that mTOR inhibition is not a straightforward strategy for improving AAV transduction. More studies are necessary to elucidate the molecular mechanisms involve in the positive and negative effects of mTOR inhibitors on AAV transduction efficiency.

A Comparison of the Cellular and Molecular Atlases of the Macaque and Mouse Dorsal Horns

SSRN Electronic Journal

2021 Sep 18

Arokiaraj, C;Kleyman, M;Chamessian, A;Shiers, S;Kang, B;Kennedy, M;Patterson, R;Lewis, D;Qadri, Y;Levine, A;Price, T;Pfenning, A;Seal, R;
| DOI: 10.2139/ssrn.3924596

The spinal dorsal horn transforms incoming somatosensory information and transmits it supraspinally to generate modality-specific sensory percepts. Understanding precisely how neurons in this region process somatosensory information in rodents, and in higher-order species such as primates, has been hampered by the incomplete identification of individual cell types. In this study, we generate a comprehensive classification scheme for molecularly defined cell types across species-from mouse to primate by performing single nucleus RNA-sequencing of the Rhesus macaque dorsal horn and comparing it to a mouse meta-analysis. A comparison of the laminar distributions of these cell types across species lends further support to this classification. Despite the high conservation, we also identify species-specific differences in the expression of key genes. The study thus provides an essential resource for the functional interrogation of neural circuits underlying somatosensory processing within the dorsal horn and across species as well as for the validation of therapeutic targets.

Astrocyte-derived neurons provide excitatory input to the adult striatal circuitry

Proceedings of the National Academy of Sciences of the United States of America

2021 Aug 17

Dorst, MC;Díaz-Moreno, M;Dias, DO;Guimarães, EL;Holl, D;Kalkitsas, J;Silberberg, G;Göritz, C;
PMID: 34389674 | DOI: 10.1073/pnas.2104119118

Astrocytes have emerged as a potential source for new neurons in the adult mammalian brain. In mice, adult striatal neurogenesis can be stimulated by local damage, which recruits striatal astrocytes into a neurogenic program by suppression of active Notch signaling (J. P. Magnusson et al., Science 346, 237-241 [2014]). Here, we induced adult striatal neurogenesis in the intact mouse brain by the inhibition of Notch signaling in astrocytes. We show that most striatal astrocyte-derived neurons are confined to the anterior medial striatum, do not express established striatal neuronal markers, and exhibit dendritic spines, which are atypical for striatal interneurons. In contrast to striatal neurons generated during development, which are GABAergic or cholinergic, most adult astrocyte-derived striatal neurons possess distinct electrophysiological properties, constituting the only glutamatergic striatal population. Astrocyte-derived neurons integrate into the adult striatal microcircuitry, both receiving and providing synaptic input. The glutamatergic nature of these neurons has the potential to provide excitatory input to the striatal circuitry and may represent an efficient strategy to compensate for reduced neuronal activity caused by aging or lesion-induced neuronal loss.

Deciphering the Mechanisms of COVID-19 Induced Anosmia

SSRN Electronic Journal

2021 Aug 14

Zazhytska, M;Kodra, A;Hoagland, D;Fullard, J;Shayya, H;Moeller, R;Uhl, S;Omer, A;Firestein, S;Gong, Q;Canoll, P;Goldman, J;Rousos, P;tenOever, B;Overdevest, J;Lomvardas, S;
| DOI: 10.2139/ssrn.3900127

SARS-CoV-2 infects less than 1% of cells in the human body, yet it can cause severe damage in a variety of organs. Thus, deciphering the non-cell autonomous effects of SARS-CoV-2 infection is imperative for understanding the cellular and molecular disruption it elicits. Neurological and cognitive defects are among the least understood symptoms of COVID-19 patients, with olfactory dysfunction being their most common sensory deficit. Here, we show that both in humans and hamsters SARS-CoV-2 infection causes widespread downregulation of olfactory receptors (OR) and of their signaling components. This non-cell autonomous effect coincides with a dramatic reorganization of the neuronal nuclear architecture, which results in dissipation of genomic OR compartments and elimination of genomic contact domains genomewide. Our data provide a novel mechanism by which SARS-CoV-2 infection alters the cellular morphology and the transcriptome of cells it cannot infect, providing insight to its systemic effects in the nervous system and beyond.

NPAS4 regulates the transcriptional response of the suprachiasmatic nucleus to light and circadian behavior

Neuron

2021 Aug 12

Xu, P;Berto, S;Kulkarni, A;Jeong, B;Joseph, C;Cox, KH;Greenberg, ME;Kim, TK;Konopka, G;Takahashi, JS;
PMID: 34416169 | DOI: 10.1016/j.neuron.2021.07.026

The suprachiasmatic nucleus (SCN) is the master circadian pacemaker in mammals and is entrained by environmental light. However, the molecular basis of the response of the SCN to light is not fully understood. We used RNA/chromatin immunoprecipitation/single-nucleus sequencing with circadian behavioral assays to identify mouse SCN cell types and explore their responses to light. We identified three peptidergic cell types that responded to light in the SCN: arginine vasopressin (AVP), vasoactive intestinal peptide (VIP), and cholecystokinin (CCK). In each cell type, light-responsive subgroups were enriched for expression of neuronal Per-Arnt-Sim (PAS) domain protein 4 (NPAS4) target genes. Further, mice lacking Npas4 had a longer circadian period under constant conditions, a damped phase response curve to light, and reduced light-induced gene expression in the SCN. Our data indicate that NPAS4 is necessary for normal transcriptional responses to light in the SCN and critical for photic phase-shifting of circadian behavior.

Potential Utility of Natural Killer Cells for Eliminating Cells Harboring Reactivated Latent HIV-1 Following the Removal of CD8+ T Cell-Mediated Pro-Latency Effect(s)

Viruses

2021 Jul 26

Khoury, G;Kulpa, DA;Parsons, MS;
PMID: 34452317 | DOI: 10.3390/v13081451

An impediment to curing HIV-1 infection is the persistence of latently infected cells in ART-treated people living with HIV (PLWH). A key strategy for curing HIV-1 infection is to activate transcription and translation of latent virus using latency reversing agents (LRAs) and eliminate cells harboring reactivated virus via viral cytopathic effect or immune clearance. In this review, we provide an overview of available LRAs and their use in clinical trials. Furthermore, we describe recent data suggesting that CD8+ T cells promote HIV-1 latency in the context of ART, even in the presence of LRAs, which might at least partially explain the clinical inefficiency of previous "shock and kill" trials. Here, we propose a novel cure strategy called "unlock, shock, disarm, and kill". The general premise of this strategy is to shut down the pro-latency function(s) of CD8+ T cells, use LRAs to reverse HIV-1 latency, counteract anti-apoptotic molecules, and engage natural killer (NK) cells to mediate the killing of cells harboring reactivated latent HIV-1.

3: Multimodal Molecular Analysis Reveals Divergent Trajectories Of Wound Regeneration Versus Fibrosis

Plastic and Reconstructive Surgery - Global Open

2021 Jul 26

desJardins-Park, H;Mascharak, S;Januszyk, M;Chen, K;Davitt, M;Demeter, J;Henn, D;Griffin, M;Bonham, C;Mooney, N;Cheng, R;Jackson, P;Wan, D;Gurtner, G;Longaker, M;
| DOI: 10.1097/01.gox.0000769936.79898.fc

RESULTS: Pseudotime analysis (Monocle3) of pooled scRNA-seq data revealed that fibroblasts followed two distinct transcriptional trajectories, one characterized by mechanical activation (_En-1_ lineage-positive, “fibrotic” trajectory) and the other characterized by developmental and regenerative pathways (_En-1_ lineage-negative; Rspo1, Dkk2/3, Trps1). Cross-platform data integration confirmed that fibroblasts in the fibrotic trajectory correlated with myofibroblast proteomic signatures (Col1a1/2, Fn1, etc.) and fibrotic/scar ECM features. In contrast, fibroblasts in the regenerative trajectory negatively correlated with myofibroblast markers and were associated with a “basket-weave” ECM pattern quantitatively indistinguishable from that of unwounded skin. Our integrated dataset suggested an important role for Wnt pathway proteins in ENF-mediated skin regeneration, so we compared POD 14 scars and regenerated wounds by multiplexed _in situ_ hybridization (RNAScope) for _Rspo1_ (Wnt agonist), _Trps1_ (master hair follicle regulator), _Ank1_ (YAP target gene), and _Dpp4_ (EPF marker). Quantification of RNA granules across thousands of cells using a custom image analysis pipeline revealed that ENF-mediated healing (low _Dpp4_) in YAP-inhibited (low _Ank1_) wounds yielded regeneration of functional hair follicles through Wnt-mediated pathway activation (high _Rpos1_, _Trps1_). These data suggest that YAP inhibition unlocks wound regeneration via Wnt-active, _En-1_ lineage-negative fibroblasts.

Cyclic growth of dermal papilla and regeneration of follicular mesenchymal components during feather cycling

Development (Cambridge, England)

2021 Jul 16

Wu, P;Jiang, TX;Lei, M;Chen, CK;Li, SH;Widelitz, RB;Chuong, CM;
PMID: 34269796 | DOI: 10.1242/dev.198671

How dermis maintains tissue homeostasis in cyclic growth and wounding is a fundamental un-solved question. Here we study how dermal components of feather follicles undergo physiological (molting) and plucking injury-induced regeneration. Proliferation analyses reveal quiescent, transient-amplifying, and long-term label-retaining dermal cell (LRDC) states. In Growth phase, LRDCs are activated to make new dermal components with distinct cellular flows. Dermal transient amplifying (TA) cells, enriched in the proximal follicle, generate (i) peripheral pulp which extends distally to expand the epithelial-mesenchymal interactive interface for barb patterning, and (ii) central pulp which provides nutrition. Entering Resting phase, LRDCs, accompanying collar bulge epidermal LRC cells, descend to the apical dermal papilla. In the next cycle, these apical derma papilla LRDCs are re-activated to become new pulp progenitor TA cells. In growth phase, lower dermal sheath can generate dermal papilla and pulp. Transcriptome analyses identify marker genes and highlight molecular signaling associated with dermal specification. We compare cyclic topological changes with that of hair follicle, a convergently evolved follicle configuration. The work presents a model for analyzing homeostasis and tissue remodeling of mesenchymal progenitors.

Mother-to-Child Transmission of Arboviruses during Breastfeeding: From Epidemiology to Cellular Mechanisms

Viruses

2021 Jul 07

Desgraupes, S;Hubert, M;Gessain, A;Ceccaldi, P;Vidy, A;
| DOI: 10.3390/v13071312

Most viruses use several entry sites and modes of transmission to infect their host (parenteral, sexual, respiratory, oro-fecal, transplacental, transcutaneous, etc.). Some of them are known to be essentially transmitted via arthropod bites (mosquitoes, ticks, phlebotomes, sandflies, etc.), and are thus named arthropod-borne viruses, or arboviruses. During the last decades, several arboviruses have emerged or re-emerged in different countries in the form of notable outbreaks, resulting in a growing interest from scientific and medical communities as well as an increase in epidemiological studies. These studies have highlighted the existence of other modes of transmission. Among them, mother-to-child transmission (MTCT) during breastfeeding was highlighted for the vaccine strain of yellow fever virus (YFV) and Zika virus (ZIKV), and suggested for other arboviruses such as Chikungunya virus (CHIKV), dengue virus (DENV), and West Nile virus (WNV). In this review, we summarize all epidemiological and clinical clues that suggest the existence of breastfeeding as a neglected route for MTCT of arboviruses and we decipher some of the mechanisms that chronologically occur during MTCT via breastfeeding by focusing on ZIKV transmission process.

Assessing proviral competence: current approaches to evaluate HIV-1 persistence

Current opinion in HIV and AIDS

2021 Jul 01

Cicilionytė, A;Berkhout, B;Pasternak, AO;
PMID: 33993171 | DOI: 10.1097/COH.0000000000000687

Despite decades of suppressive antiretroviral therapy (ART), HIV-1 reservoirs persist and fuel viral rebound if therapy is interrupted. The persistence of viral reservoirs in infected individuals is the main obstacle to achieving HIV-1 eradication or a long-term remission. Accurate assessment of the viral reservoir size is necessary for monitoring the effectiveness of the curative interventions. Here, we review the recent progress in the development of assays to measure HIV-1 persistence, highlighting their key advantages and limitations.To estimate the viral reservoir size, a number of assays have been developed that assess different aspects of HIV-1 persistence in ART-treated individuals. These include viral outgrowth assays to measure proviral replication competence, sequencing-based assays to measure genetic intactness of HIV-1 proviruses, and diverse techniques that measure the ability of proviruses to produce viral RNA and/or proteins (transcription and translation competence), with or without ex vivo stimulation. Recent years have seen the development of next-generation reservoir assays that, in addition to measuring viral persistence markers, assess the proviral integration sites and characterize the HIV-1 reservoir cells on the single-cell level.Although no assay yet can measure the HIV-1 reservoir with 100% accuracy, recent technical advances allow reliable estimation of its size and composition.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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