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1.
J Gastrointest Oncol ; 15(1): 478-484, 2024 Feb 29.
Artículo en Inglés | MEDLINE | ID: mdl-38482230

RESUMEN

Background: Small molecule fibroblast growth factor receptor (FGFR) inhibitors, such as pemigatinib, have been developed for the treatment of cholangiocarcinoma (CCA) with rearrangements or fusions in the FGFR2. FGFR inhibitors (FGFRis) have dermatologic side effects such as dry skin or nail bed damage. However, in very rare instances, a life-threatening vascular calcification disease known as calciphylaxis has been linked to these therapies. Case Description: We report a patient with metastatic CCA, who developed calciphylaxis following the start of their pemigatinib treatment. Calciphylaxis is associated with skin lesions and affects the dermal microvasculature in addition to the vascular calcification. This case focuses on the management strategy used for this rare adverse event (AE) as well as the pathology and complicated mechanism of calciphylaxis. We highlight the unclear pathophysiology behind this disease by identifying key players in the signaling and molecular pathways in the microenvironment that are needed to trigger this pathology. Conclusions: Calciphylaxis is normally associated with advanced renal failure in the setting of high phosphate and calcium. However, the patient we present here did not have advanced renal failure or high calcium levels and calcium dysregulation. As FGFRi use becomes more widespread, the more important it becomes to identify and have a treatment strategy for this rare AE.

2.
Expert Opin Investig Drugs ; 30(10): 1047-1056, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34579607

RESUMEN

INTRODUCTION: The development of novel biomarkers for cancer has exploded over the last decade with advances in novel technologies. Cholangiocarcinoma (CCA), a cancer of the bile ducts, has a dearth of strong disease and pathophysiology biomarkers, making early detection and prognostication a difficult task. AREAS COVERED: In this comprehensive review, we discuss the spectrum of biomarkers for CCA diagnosis and prognostication. We elaborate on novel biomarker discovery through a comprehensive multi-omics approach. We also cover, how certain biomarkers may also serve as unique and potent targets for therapeutic development. EXPERT OPINION: Despite the relatively poor diagnostic and prognostic performance of existing biomarkers for CCA, there is a vast range of novel biomarkers with exquisite diagnostic and prognostic performance for CCA in the pipeline. Moreover, these biomarkers may serve as potential targets for precision medicine. Existing strategies to target unique biomolecular classes are discussed, within the context of an overall 'omics' focused profiling strategy. Omics profiling will simultaneously allow for enhanced biomarker development and identification of unique subtypes of cholangiocarcinoma and how they are influenced by an individual's unique context. In this manner, patient management strategy and clinical trial design can be optimized to the individual.


Asunto(s)
Neoplasias de los Conductos Biliares/diagnóstico , Biomarcadores de Tumor/metabolismo , Colangiocarcinoma/diagnóstico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/patología , Desarrollo de Medicamentos , Drogas en Investigación/farmacología , Humanos , Medicina de Precisión , Pronóstico
3.
Nat Genet ; 51(12): 1714-1722, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31784732

RESUMEN

Core regulatory transcription factors (CR TFs) orchestrate the placement of super-enhancers (SEs) to activate transcription of cell-identity specifying gene networks, and are critical in promoting cancer. Here, we define the core regulatory circuitry of rhabdomyosarcoma and identify critical CR TF dependencies. These CR TFs build SEs that have the highest levels of histone acetylation, yet paradoxically the same SEs also harbor the greatest amounts of histone deacetylases. We find that hyperacetylation selectively halts CR TF transcription. To investigate the architectural determinants of this phenotype, we used absolute quantification of architecture (AQuA) HiChIP, which revealed erosion of native SE contacts, and aberrant spreading of contacts that involved histone acetylation. Hyperacetylation removes RNA polymerase II (RNA Pol II) from core regulatory genetic elements, and eliminates RNA Pol II but not BRD4 phase condensates. This study identifies an SE-specific requirement for balancing histone modification states to maintain SE architecture and CR TF transcription.


Asunto(s)
Histonas/metabolismo , Rabdomiosarcoma/genética , Factores de Transcripción/genética , Acetilación , Benzamidas/farmacología , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Elementos de Facilitación Genéticos , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Redes Reguladoras de Genes , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Histonas/genética , Humanos , Piridinas/farmacología , ARN Polimerasa II/genética , ARN Polimerasa II/metabolismo , Estabilidad del ARN , Factores de Transcripción SOXE/genética , Análisis de la Célula Individual
4.
Nat Commun ; 10(1): 1501, 2019 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-30940810

RESUMEN

Riboswitches are naturally occurring RNA aptamers that regulate gene expression by binding to specific small molecules. Riboswitches control the expression of essential bacterial genes and are important models for RNA-small molecule recognition. Here, we report the discovery of a class of synthetic small molecules that bind to PreQ1 riboswitch aptamers. These molecules bind specifically and reversibly to the aptamers with high affinity and induce a conformational change. Furthermore, the ligands modulate riboswitch activity through transcriptional termination despite no obvious chemical similarity to the cognate ligand. X-ray crystallographic studies reveal that the ligands share a binding site with the cognate ligand but make different contacts. Finally, alteration of the chemical structure of the ligand causes changes in the mode of RNA binding and affects regulatory function. Thus, target- and structure-based approaches can be used to identify and understand the mechanism of synthetic ligands that bind to and regulate complex, folded RNAs.


Asunto(s)
Aptámeros de Nucleótidos/química , Aptámeros de Nucleótidos/metabolismo , Pirimidinonas/química , Pirimidinonas/metabolismo , Pirroles/química , Pirroles/metabolismo , Riboswitch , Aptámeros de Nucleótidos/genética , Cristalografía por Rayos X , Ligandos , Conformación de Ácido Nucleico , Pirimidinonas/síntesis química , Pirroles/síntesis química , Pliegue del ARN
5.
SLAS Discov ; 22(6): 760-766, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28346086

RESUMEN

E2 enzymes in ubiquitin-like conjugation pathways are important, highly challenging pharmacological targets, and despite significant efforts, few noncovalent modulators have been discovered. Small-molecule microarray (SMM)-based screening was employed to identify an inhibitor of the "undruggable" small ubiquitin-like modifier (SUMO) E2 enzyme Ubc9. The inhibitor, a degradation product from a commercial screening collection, was chemically synthesized and evaluated in biochemical, mechanistic, and structure-activity relationship studies. Binding to Ubc9 was confirmed through the use of ligand-detected nuclear magnetic resonance, and inhibition of sumoylation in a reconstituted enzymatic cascade was found to occur with an IC50 of 75 µM. This work establishes the utility of the SMM approach for identifying inhibitors of E2 enzymes, targets with few known small-molecule modulators.


Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Bibliotecas de Moléculas Pequeñas , Enzimas Ubiquitina-Conjugadoras/antagonistas & inhibidores , Cromatografía Liquida , Descubrimiento de Drogas/métodos , Humanos , Espectrometría de Masas , Estructura Molecular , Transducción de Señal , Relación Estructura-Actividad , Sumoilación , Enzimas Ubiquitina-Conjugadoras/química , Enzimas Ubiquitina-Conjugadoras/metabolismo
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