RESUMEN
Leiomyosarcomas (LMS) are genetically heterogeneous tumors differentiating along smooth muscle lines. Currently, LMS treatment is not informed by molecular subtyping and is associated with highly variable survival. While disease site continues to dictate clinical management, the contribution of genetic factors to LMS subtype, origins, and timing are unknown. Here we analyze 70 genomes and 130 transcriptomes of LMS, including multiple tumor regions and paired metastases. Molecular profiling highlight the very early origins of LMS. We uncover three specific subtypes of LMS that likely develop from distinct lineages of smooth muscle cells. Of these, dedifferentiated LMS with high immune infiltration and tumors primarily of gynecological origin harbor genomic dystrophin deletions and/or loss of dystrophin expression, acquire the highest burden of genomic mutation, and are associated with worse survival. Homologous recombination defects lead to genome-wide mutational signatures, and a corresponding sensitivity to PARP trappers and other DNA damage response inhibitors, suggesting a promising therapeutic strategy for LMS. Finally, by phylogenetic reconstruction, we present evidence that clones seeding lethal metastases arise decades prior to LMS diagnosis.
Asunto(s)
Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad/genética , Genómica/métodos , Leiomiosarcoma/genética , Músculo Liso/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Evolución Clonal , Estudios de Cohortes , Femenino , Humanos , Leiomiosarcoma/clasificación , Leiomiosarcoma/diagnóstico , Masculino , Persona de Mediana Edad , Músculo Liso/patología , Mutación , RNA-Seq/métodos , Análisis de SupervivenciaRESUMEN
The asymmetric synthesis of all four of the known natural phlegmarines and one synthetic derivative has been accomplished in 19-22 steps from 4-methoxy-3-(triisopropylsilyl)pyridine. Chiral N-acylpyridinium salt chemistry was used twice to set the stereocenters at the C-9 and C-2' positions of the phlegmarine skeleton. Key reactions include the use of a mixed Grignard reagent for the second N-acylpyridinium salt addition, zinc/acetic acid reduction of a complex dihydropyridone, and a von Braun cyanogen bromide N-demethylation of a late intermediate. These syntheses confirmed the absolute stereochemistry of all of the known phlegmarines.
Asunto(s)
Alcaloides/síntesis química , Alcaloides/química , Indicadores y Reactivos/química , Espectroscopía de Resonancia Magnética , Conformación Molecular , Estructura Molecular , EstereoisomerismoRESUMEN
We developed a novel taxane-binding peptide (TBP) modified, biodegradable polymeric micelle that overcomes limitations of drug loading and poor serum stability typically seen with particle delivery, leading to enhanced pharmacokinetics and tumor distribution of docetaxel (DTX). The use of the taxane-binding peptide to increase docetaxel loading is particularly compelling as it takes advantage of a known intracellular binding mechanism in a new way. Docetaxel is a potent chemotherapeutic with a therapeutic index often limited by the toxicity of the excipients that are necessary to enhance its solubility for intravenous delivery. Our polymeric micelle has terminal furan groups that enable facile antibody Fab conjugation by Diels-Alder chemistry for targeted delivery. Compared to the conventional ethanolic polysorbate 80 formulation (Free DTX), our nanoparticle (NP DTX) formulation exhibited a two-fold increase in exposure and tumor accumulation. Notably, the reduced toxicity of the NP DTX formulation increased the therapeutic index and allowed for higher dosing regimens, with a maximum tolerated dose (MTD) 1.6-fold higher than that of the Free DTX formulation, which is significant and similar to enhancements observed in clinical products for docetaxel and other drugs. These improved properties led to enhanced mouse survival in an orthotopic model of breast cancer; however, the targeted formulation of Fab-NP DTX did not further improve efficacy. Together, these results clearly demonstrate the benefits of the TBP-modified polymeric micelles as promising carriers for docetaxel.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Nanocápsulas/administración & dosificación , Nanocápsulas/química , Péptidos/química , Taxoides/administración & dosificación , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Neoplasias de la Mama/patología , Línea Celular Tumoral , Docetaxel , Evaluación Preclínica de Medicamentos , Emulsiones , Femenino , Ratones , Micelas , Polímeros/química , Unión Proteica , Taxoides/química , Resultado del TratamientoRESUMEN
Cryptophycin 52 (LY355703) is a potent antiproliferative analogue of the marine natural product cryptophycin 1. It has been shown to have a broad range of antitumor activity against human tumor xenografts and murine tumors including tumors resistant to Taxol and Adriamycin. Its mechanism of action involves arresting cells in the G2-M phase of the cell cycle by binding to microtubules and suppressing their dynamics. This 16-membered depsipeptide can be divided into four major subunits or fragments (A-D). We reported previously on our synthetic efforts around fragment A and discovered that this region of the molecule was amenable to a structure-activity relationship study that resulted in highly active antiproliferative agents when evaluated in the CEM leukemia cell line. The synthetic analogues were designed to help improve the efficacy and aqueous solubility of the parent compound; therefore, many in this series contained ionizable functional groups such as an amino group, a hydroxy group, or a carboxylic acid. Although several of these analogues showed improvements in potency over cryptophycin 52 in drug-sensitive tumor xenograft models, many lost their activity against Adriamycin-resistant tumor lines. It was discovered on additional in vitro evaluation that these analogues became good substrates of the multidrug resistance transporter P-glycoprotein.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacología , Depsipéptidos/química , Depsipéptidos/farmacología , Lactamas/química , Lactamas/farmacología , Lactonas/química , Lactonas/farmacología , Línea Celular Tumoral , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Humanos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cryptophycin 52 is a synthetic derivative of Cryptophycin 1, a potent antimicrotubule agent isolated from cyanobacteria. In an effort to increase the potency and water solubility of the molecule, a structure-activity relationship study (SAR) was initiated around the phenyl ring of fragment A. These Cryptophycin 52 analogues were accessed using a Wittig olefination reaction between various triphenylphosphonium salts and a key intermediate aldehyde prepared from Cryptophycin 53. Substitution on the phenyl ring of fragment A was well tolerated, and several of these analogues were equally or more potent than Cryptophycin 52 when evaluated in vitro in the CCRF-CEM leukemia cell line and in vivo against a murine pancreatic adenocarcinoma.
Asunto(s)
Antineoplásicos/síntesis química , Depsipéptidos , Lactamas/síntesis química , Lactonas/síntesis química , Adenocarcinoma/tratamiento farmacológico , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Lactamas/química , Lactamas/farmacología , Lactonas/química , Lactonas/farmacología , Masculino , Ratones , Trasplante de Neoplasias , Neoplasias Pancreáticas/tratamiento farmacológico , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Drug delivery to solid tumours remains a challenge because both tumour physiology and drug solubility are unfavourable. Engineered materials can provide the basis for drug reformulation, incorporating active compounds and modulating their pharmacokinetic and biodistribution behaviour. To this end, we encapsulated docetaxel, a poorly soluble taxane drug, in a self-assembled polymeric nanoparticle micelle of poly(2-methyl-2-carboxytrimethylene carbonate-co-D,L-lactide)-graft-poly(ethylene glycol) (poly(TMCC-co-LA)-g-PEG). This formulation was compared with its conventional ethanolic polysorbate 80 formulation in terms of plasma circulation and biodistribution in an orthotopic mouse model of breast cancer. Notably, the polymeric nanoparticle formulation achieved greater tumour retention, resulting in prolonged exposure of cancer cells to the active drug. This behaviour was unique to the tumour tissue. The active drug was eliminated at equal or greater rates in all other tissues assayed when delivered in the polymeric nanoparticles vs. the free drug formulation. Thus, these polymeric nanoparticles are promising vehicles for solid tumour drug delivery applications, offering greater tumour exposure while eliminating the need for toxic solvents and surfactants in the dosing formulation.
Asunto(s)
Antineoplásicos/uso terapéutico , Carbonatos/química , Dioxanos/química , Sistemas de Liberación de Medicamentos , Micelas , Neoplasias/tratamiento farmacológico , Polietilenglicoles/química , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Carbonatos/metabolismo , Dioxanos/metabolismo , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Femenino , Ensayo de Materiales , Ratones , Ratones Endogámicos NOD , Ratones SCID , Estructura Molecular , Trasplante de Neoplasias , Neoplasias/metabolismo , Neoplasias/patología , Polietilenglicoles/metabolismo , Distribución TisularRESUMEN
Cryptophycins-1 and 52 (epoxides) were discovered to have in-vitro and in-vivo antitumor activity in the early 1990s. The chlorohydrins of these, Cryptophycins-8 and 55 (also discovered in the early 1990s) were markedly more active, but could not be formulated as stable solutions. With no method to adequately stabilize the chlorohydrins at the time, Cryptophycin-52 (LY 355073) entered clinical trials, producing only marginal antitumor activity. Since that time, glycinate esters of the hydroxyl group of the chlorohydrins have been synthesized and found to provide stability. Three of the most active were compared herein. Cryptophycin-309 (C-309) is a glycinate ester of the chlorohydrin Cryptophycin-296. The glycinate derivative provided both chemical stability and improved aqueous solubility. After the examination of 81 different Cryptophycin analogs in tumor bearing animals, C-309 has emerged as superior to all others. The following %T/C and Log Kill (LK) values were obtained from a single course of IV treatment (Q2d x 5) against early staged SC transplantable tumors of mouse and human origin: Mam 17/Adr [a pgp (+) MDR tumor]: 0%T/C, 3.2 LK; Mam 16/C/Adr [a pgp (-) MDR tumor]: 0%T/C, 3.3 LK; Mam 16/C: 0%T/C, 3.8 LK; Colon 26: 0%T/C, 2.2 LK; Colon 51: 0%T/C, 2.4 LK; Pancreatic Ductal Adenocarcinoma 02 (Panc 02): 0%T/C, 2.4 LK; Human Colon HCT15 [a pgp (+) MDR tumor]: 0%T/C, 3.3 LK; Human Colon HCT116: 0%T/C, 4.1 LK. One additional analog, Cryptophycin-249 (C-249, the glycinate of Cryptophycin-8), also emerged with efficacy rivaling or superior to C-309. However, there was sufficient material for only a single C-249 trial in which a 4.0 LK was obtained against the multidrug resistant breast adenocarcinoma Mam-16/C/Adr. C-309 and C-249 are being considered as second-generation clinical candidates.
Asunto(s)
Antineoplásicos/farmacología , Depsipéptidos/farmacología , Compuestos Epoxi/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Péptidos Cíclicos/farmacología , Animales , Antineoplásicos/química , Depsipéptidos/química , Ensayos de Selección de Medicamentos Antitumorales , Compuestos Epoxi/química , Ésteres , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ratones SCID , Trasplante de Neoplasias , Péptidos Cíclicos/química , Relación Estructura-ActividadRESUMEN
Synthesis of indolo[6,7-a]pyrrolo[3,4-c]carbazoles 1, a new class of cyclin D1/CDK4 inhibitors, by oxidation of the corresponding aryl indolylmaleimides 2, will be described. Two approaches to the synthesis of 2 were identified that required new methods for the synthesis of 7-substituted indole acetamides 3 and N-methyl (indol-7-yl)oxoacetates 6. The chemistry developed enabled introduction of functionality (-OR, NR(2)) at C(12) and N(13) facilitating structure-activity relationship (SAR) evaluation of this indolocarbazole platform.
Asunto(s)
Antineoplásicos/síntesis química , Carbazoles/síntesis química , Ciclina D1/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Indoles/química , Proteínas Proto-Oncogénicas , Pirroles/química , Acetamidas/química , Acetatos/química , Quinasa 4 Dependiente de la Ciclina , Humanos , Maleimidas/química , Oxidantes/química , Fotoquímica , Relación Estructura-ActividadRESUMEN
The synthesis of a novel series of 1,7-annulated indolocarbazoles 2 and 16 is described. These compounds were found to be potent cyclin dependent kinase inhibitors with good antiproliferative activity against two human carcinoma cell lines. These inhibitors also arrested tumor cells at the G1 phase and inhibited pRb phosphorylation.
Asunto(s)
Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Indoles/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Quinasas Ciclina-Dependientes/metabolismo , Inhibidores de Crecimiento/síntesis química , Inhibidores de Crecimiento/farmacología , Humanos , Indoles/farmacología , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
The synthesis and kinase inhibitory activity of a series of novel 1,7-annulated indolocarbazoles 6 and 16 is described. These compounds exhibited potent inhibitory activity against cyclin-dependent kinase 4 and good antiproliferative activity in a human colon carcinoma cell line.
Asunto(s)
Carbazoles/química , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Indoles/química , Inhibidores de Proteínas Quinasas/química , Carbazoles/farmacología , Ciclina D1/antagonistas & inhibidores , Ciclina D1/metabolismo , Quinasa 4 Dependiente de la Ciclina , Quinasas Ciclina-Dependientes/metabolismo , Indoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismoRESUMEN
The synthesis of novel aza-1,7-annulated indoles was achieved and these were converted to indolocarbazoles that proved to be potent kinase inhibitors. These compounds were also evaluated in a human colon carcinoma cell line and proved to be good antiproliferative agents.