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Tipo: Otros inhibidores

Grupo de fármacos que inhiben diferentes rutas como: la vía de la MAPK, vía IP3-DAG o vía inositol trifosfato (PI3)-quinasa; asociadas a receptores principalmente de la tirosina-quinasa RPTK (VEGFR, EGFR, PDGFR, MET), al proteosoma, a la ruta del mTOR, la vía Hedgehog, la vía Notch, a la proteína resultante de la fusión BCR-ABL o a las moléculas de adhesión celular como son la ICAM-1, la VCAM-1 y la E-selectina u otras proteínas o rutas mitogénicas.

Categoría: Tirosina quinasa

El receptor de tirosina quinasa es un receptor celular asociado a una vía de señalización intracelular caracterizado por pertenecer a la familia de los receptores con actividad enzimática intrínseca o asociada y por poseer como ligandos a la insulina, al factor de crecimiento epidérmico, al factor de crecimiento de fibroblastos, neurotrofinas y a otros factores tróficos. Las características moleculares del receptor de tirosina quinasa comprenden la posesión de una hélice alfa transmembranal individual, aunque la proteína intrínseca posee un dominio citosólico con actividad de tirosina quinasa, y su vía de transducción de señal incluye a la proteína G monomérica Ras asociada a la MAPK, vía IP3-DAG o vía inositol trifosfato (PI3)-quinasa. De este modo, su activación mediante un estímulo externo provoca una cascada interna de reacciones enzimáticas que facilita la adaptación de la célula a su entorno, por mediación de mensajeros secundarios.

Categoría 2: ALK

Quinasa de linfoma anaplásico (ALK) también conocido como el receptor de la tirosina cinasa ALK o CD246 (grupo de diferenciación 246) es una enzima que en los humanos está codificada por el gen ALK. [2] [3]

Función

ALK desempeña un papel importante en el desarrollo del cerebro y ejerce sus efectos sobre neuronas específicas en el sistema nervioso. [3]

Las secuencias de aminoácidos deducidas revelan que ALK es un nuevo receptor tirosina quinasa que tiene un dominio transmembrana y un dominio extracelular. Estas secuencias están ausentes en el producto de la transformación de NPM-ALK gen. ALK muestra mayor similitud de secuencia a LTK (tirosina quinasa de leucocitos).

Patología

El gen ALK puede ser oncogénico de dos maneras - en primer lugar, mediante la formación de un gen de fusión con cualquiera de los otros genes, y segundo, con mutaciones en el código de ADN para el mismo gen anaplásico de células grandes linfoma

El 2, 5 translocación cromosómica se asocia con aproximadamente el 60% ​​linfomas anaplásicos de células grandes (ALCLs). El desplazamiento crea un gen de fusión que consta de la ALK (cinasa del linfoma anaplásico) y la nucleofosmina (NPM): la mitad 3' de ALK, derivado del cromosoma 2 y que codifica para el dominio catalítico, se fusiona a la porción 5' del NPM del cromosoma 5.
El producto del gen de fusión NPM-ALK es oncogénico.

http://en.wikipedia.org/wiki/Anaplastic_lymphoma_kinase

Gen que elabora una proteína que se llama cinasa de linfoma anaplásico (ALK), que puede participar en la formación de células. Las formas mutadas (cambiadas) del gen y la proteína ALK se encontraron en algunos tipos de cáncer como el neuroblastoma, el cáncer de pulmón de células no pequeñas y el linfoma de células grandes anaplásico. Estos cambios pueden aumentar la formación de células cancerosas. Si se verifica que está el gen de cinasa del linfoma anaplásico en el tejido tumoral, ello puede ayudar a planificar el tratamiento. También se llama gen ALK.

Diana:ALK

Quinasa de linfoma anaplásico (ALK) también conocido como el receptor de la tirosina cinasa ALK o CD246 (grupo de diferenciación 246) es una enzima que en los humanos está codificada por el gen ALK. [2] [3]

Función

ALK desempeña un papel importante en el desarrollo del cerebro y ejerce sus efectos sobre neuronas específicas en el sistema nervioso. [3]

Las secuencias de aminoácidos deducidas revelan que ALK es un nuevo receptor tirosina quinasa que tiene un dominio transmembrana y un dominio extracelular. Estas secuencias están ausentes en el producto de la transformación de NPM-ALK gen. ALK muestra mayor similitud de secuencia a LTK (tirosina quinasa de leucocitos).

Patología

El gen ALK puede ser oncogénico de dos maneras - en primer lugar, mediante la formación de un gen de fusión con cualquiera de los otros genes, y segundo, con mutaciones en el código de ADN para el mismo gen anaplásico de células grandes linfoma

El 2, 5 translocación cromosómica se asocia con aproximadamente el 60% ​​linfomas anaplásicos de células grandes (ALCLs). El desplazamiento crea un gen de fusión que consta de la ALK (cinasa del linfoma anaplásico) y la nucleofosmina (NPM): la mitad 3' de ALK, derivado del cromosoma 2 y que codifica para el dominio catalítico, se fusiona a la porción 5' del NPM del cromosoma 5.
El producto del gen de fusión NPM-ALK es oncogénico.

http://en.wikipedia.org/wiki/Anaplastic_lymphoma_kinase

Nombre:

Crizotinib

Comercial:

Xalkori ®

Estado: Aprobado

Tratamientos aprobados por los diferentes organismos públicos y agencias de regulación sanitarias.

Tecnología: Molécula pequeña

Foto:

Fórmula:

Gráfico:

Información: 09 Sep. 2011
La FDA aprueba Xalkori (crizotinib) como terapia para el cáncer de pulmón no microcítico

Pfizer ha recibido también la aceptación de la Agencia Europea del Medicamento (EMA) para la evaluación del registro de crizotinib y bosutinib.

La FDA ha aprobado crizotinib para el tratamiento de pacientes con cáncer de pulmón no microcítico (CPNM) con alteraciones en el gen de la kinasa del linfoma anaplásico (ALK – por sus siglas en inglés).

“El cáncer de pulmón es el carcinoma que más muertes causa cada año en todo el mundo. La aprobación de crizotinib supone un paso adelante en el tratamiento de esta enfermedad devastadora, ya que representa una nueva opción terapéutica para este subgrupo de pacientes oncológicos”, asegura Ian Read, presidente y CEO de Pfizer.

En consonancia con las últimas directrices de la FDA respecto a las terapias dirigidas y los métodos de diagnóstico complementarios, Pfizer ha colaborado estrechamente con la FDA y ha trabajado con Laboratorios Abbot para facilitar la revisión y aprobación del test ALK Break Apart FISH Probe Kit para el diagnóstico del estado de ALK. Por primera vez, un medicamento destinado a tratar el cáncer de pulmón y un test diagnóstico son desarrollados y aprobados paralelamente.

"El tratamiento con crizotinib en pacientes ALK-positivo determinado por la tecnología FISH (Fluorescence In Situ Hybridization) representa un gran avance en la medicina individualizada del cáncer de pulmón. Mediante la determinación de ALK somos capaces de identificar un grupo de pacientes que tiene unas elevadas posibilidades de beneficiarse de un tratamiento dirigido y que, además, está asociado con una excelente tolerancia. En el abordaje actual del cáncer de pulmón necesitamos la determinación de marcadores moleculares para la optimización del tratamiento", explica la doctora Enriqueta Felip, Jefe de Sección del Servicio de Oncología Médica del Hospital Vall d'Hebron.

Evidencia clínica
La decisión de la FDA se sustenta en los datos procedentes de dos estudios multicéntricos de un solo brazo en los que han participado un total de 255 pacientes con CPNM en estado avanzado y ALK positivo.

El estudio PROFILE 1005 se desarrolló con una muestra de 136 pacientes y la mediana de duración del tratamiento fue de 22 semanas. En este trabajo, la tasa de respuesta objetiva (TRO) fue del 50 por ciento, incluyendo una respuesta completa y 67 respuestas parciales. El 79 por ciento de las respuestas objetivas tumorales se produjeron durante las primeras ocho semanas del tratamiento. La mediana de duración de la respuesta fue de 41,9 semanas.

En el Estudio 1001 participaron 119 pacientes. La TRO fue del 61 por ciento, incluyendo dos respuestas completas y 69 parciales. La mediana de duración del tratamiento fue de 32 semanas. El 55 por ciento de las respuestas objetivas tumorales se produjeron en las primeras 8 semanas de tratamiento. La mediana de duración de la respuesta fue de 48,1 semanas.

Avances en los procesos de evaluación europeos
Además de la aprobación de crizotinib por la FDA, Pfizer ha recibido la aceptación de la EMA para revisar la solicitud de registro de este medicamento. Asimismo, este organismo regulador ha admitido la solicitud de la compañía biomédica para el estudio de bosutinib como tratamiento en adultos recientemente diagnosticados con Leucemia Mieloide Crónica con cromosoma Filadelfia positivo en fase crónica.

“La respuesta de la EMA en relación a crizotinib y bosutinib es un paso más para poder ofrecer a los pacientes dos terapias prometedoras en áreas en las que existen necesidades médicas sin cubrir”, afirma el doctor Andreas Penk, presidente de la Unidad de Oncología de Pfizer en Europa. “Las solicitudes que hemos presentado a la Agencia son una prueba de nuestro compromiso para proporcionar opciones terapéuticas innovadoras frente a varios tipos de tumores y mejorar los resultados de los tratamientos en todo el mundo”.

http://www.pmfarma.es/noticias/13745-la-fda-aprueba-xalkori-crizotinib-como-terapia-para-el-cancer-de-pulmon-no-microcitico.html

ALK inhibitors, a pharmaceutical perspective
Elena Ardini* and Arturo Galvani

Department of Cell Biology, Oncology, Nerviano Medical Sciences, Milan, Italy

In 2007, the ALK tyrosine kinase was described as a potential therapeutic target for a subset of non-small-cell lung cancer patients. Clinical proof of concept, culminating in the recent approval by the Food and Drug Administration of the Pfizer drug crizotinib followed in record time. The drug was approved together with a companion diagnostic for detection of patients eligible for therapy. This remarkable example of the coming of age of personalized medicine in cancer therapy is hopefully only an auspice of things to come in a rapidly developing field. Perhaps unsurprisingly, however, the appearance of clinical acquired resistance to crizotinib was observed early on in clinical testing, with the identification of several ALK secondary point mutations which diminish drug efficacy and which open the way for development of second-generation inhibitors. It is also emerging that acquired resistance to crizotinib may additionally occur through ALK-independent mechanisms, which still need to be elucidated in detail. Here we discuss the factors that led to such a rapid approval of a targeted agent, and we describe the second-generation compounds currently in development.
Introduction

The ALK (anaplastic lymphoma kinase) gene encodes a tyrosine kinase belonging to the insulin receptor superfamily. ALK is abundantly expressed in neural tissue during embryogenesis, but levels fall during early development, so that in adults it is expressed only in rare scattered neural cells (Iwahara et al., 1997; Morris et al., 1997; Webb et al., 2009; Ardini et al., 2010). ALK was originally identified in anaplastic large cell lymphoma (ALCL) cells as the product of a recurring chromosomal translocation, t(2;5; p23;q35), between the ALK gene on chromosome 2 and the nucleophosmin (NPM) gene on chromosome 5, which gives rise to expression of the NPM–ALK fusion protein (Morris et al., 1994). The oncogenic potential of NPM–ALK, which contains a constitutively activated ALK kinase domain, was subsequently demonstrated in several different preclinical models, confirming its role in the pathogenesis of ALCL (Shiota et al., 1994; Drexler et al., 2000). In addition to ALCL, ALK gene translocations or activating point mutations were identified in other rare tumor types, including inflammatory myofibroblastic tumors (IMT) and neuroblastoma (Webb et al., 2009; Ardini et al., 2010). IMT is a rare tumor of mesenchymal origin that affects young individuals, with approximately 50% of cases bearing a chromosomal translocation involving the ALK gene, fused to many different N-terminal partners (Griffin et al., 1999), while neuroblastoma is a rare pediatric solid tumor and originates from neural cell-derived tissue, giving tumor masses localized mainly at the level of the adrenal glands (Maris et al., 2007). In neuroblastoma, ALK gene amplification and point mutations are found as recurring events, rather than gene translocation.

Notwithstanding the substantial evidence linking activated ALK kinase to tumorigenesis in these rare tumors, it is fair to say that the considerable current enthusiasm for ALK as target for cancer therapy is largely driven by the relatively recent finding of a recurring ALK gene translocation in a significant subset (ca. 5%) of non-small-cell lung cancer (NSCLC, Rikova et al., 2007; Soda et al., 2007). In ALK-positive NSCLC, ALK gene rearrangement most often involves an inversion within the short arm of chromosome 2 (between loci 2p21 and 2p23), leading to expression of echinoderm microtubule associated protein like 4 (EML4)–ALK, an oncogenic fusion protein composed of the N-terminal portion of EML4 and the entire intracellular portion of ALK. As with NPM–ALK, there is much convincing preclinical evidence in support of the oncogenic nature of EML4–ALK, the requirement for ALK kinase activity in maintenance of EML4–ALK-dependent tumor cell growth and of the capacity of selective small molecule kinase inhibitors of ALK to induce cell death in such tumors (Christensen et al., 2007; Galkin et al., 2007; Choi et al., 2008; Koivunen et al., 2008; McDermott et al., 2008; Soda et al., 2008). Subsequent studies of tissue samples from NSCLC patients aimed at further characterizing ALK-positive NSCLC have led to the identification of a relatively well defined potential patient population, characterized by specific clinical–pathological features. It appears that ALK-positive patients tend to be younger than the median age for lung cancer patients and are, in general, never-smokers, or former light smokers, while at the histological level, ALK-positive tumors are almost exclusively adenocarcinomas, with a clear component of the signet-ring cell type (Inamura et al., 2008; Shaw et al., 2009; Solomon et al., 2009; Kwak et al., 2010). The presence of EML4–ALK rearrangement appears to be mutually exclusive with KRAS and EGFR mutations, further supporting a role for ALK as a unique driver of malignancy in these patients, though interestingly, an exception is possibly represented by the recent description of a small fraction of crizotinib-naïve patients reported to possess both EML4–ALK rearrangement and EGFR mutations (Sasaki et al., 2011), as will be further commented below.
Clinical Validation of ALK as a Therapeutic Target in ALK-Positive NSCLC

Crizotinib is an orally available drug that was originally discovered and optimized as an inhibitor of c-Met kinase (Christensen et al., 2007; Zou et al., 2007). Prior to designation of the International Non-proprietary Name of “crizotinib” the drug was known as PF-02341066 (the Pfizer company’s chemical collection number for the compound) and it is now also known as Xalkori®, a Pfizer brand name, but we will subsequently only refer to it in this text as crizotinib. Studies with c-Met kinase revealed that crizotinib has a classical ATP-competitive mechanism of action and as is often the case for such inhibitors, it was subsequently found to cross-react with a few “off-target” kinases. In particular, potent activity of the drug on ALK was revealed through selectivity profiling in biochemical assay and ALK-driven cellular models (Christensen et al., 2007). A multi-indication Phase I clinical trial of crizotinib in solid tumors and lymphomas had already been initiated, with the drug described as a “c-Met/Hepatocyte Growth Factor tyrosine kinase inhibitor” (ClinicalTrials.gov Identifier: NCT00585195), when identification of the genetic rearrangement involving ALK in NSCLC was first reported (Soda et al., 2007). In 2008, while preclinical data supporting a therapeutic rationale for targeting ALK in NSCLC was still emerging, ALK-positive patients started to be enrolled in this already ongoing Phase I trial. ALK cross-reactivity of crizotinib, apparently initially seen as a possible path for registration of the compound in niche indications such as chemotherapy resistant ALCL, now became a major opportunity. Thus, patient screening and enrollment of ALK-positive subjects into the trial was initiated, using a methodology based on the break apart probe FISH (fluorescent in situ hybridization) technique, with a kit specifically developed for detecting ALK translocation in patient tumor samples (Perner et al., 2008). Within a few months, impressive preliminary data on clinical response in these patients became available. A dedicated Phase I/II clinical trial focused on ALK-positive NSCLC patients was completed in 2010 (Kwak et al., 2010), barely 3 years after the first description of this genetic lesion. After the standard dose escalation Phase I that defined the recommended dose of 250 mg twice a day per 28-day cycle, an expanded cohort of ALK-positive NSCLC was selected for treatment. Approximately 1500 NSCLC patients were screened by FISH, identifying 82 patients considered eligible and then enrolled in the expanded cohort study. Most of these patients had received previous therapy and almost half were heavily pre-treated. The overall objective response rate in this study was 57% (47 out of 82 patients, with 46 confirmed partial response and 1 complete response), with a further 33% of patients (27 out of 82) in stable disease. The estimated probability of 6-month progression-free survival was 72%. To date, the median overall survival time from initiation of crizotinib has not been determined, but 1-year overall survival was 74% and 2-year overall survival was 54% (Kwak et al., 2010; Shaw et al., 2011).

The spectacular efficacy observed for crizotinib in this challenging setting was associated with relatively mild side effects. The most frequently reported were gastrointestinal toxicities, with grade 1 nausea and diarrhea and visual disturbances, but with no abnormalities detected in ophthalmological examination. Increased levels of hepatic transaminases were also observed, but only reaching grade 3 in a limited number of patients (5 and 6% for ALT and AST, respectively). Two randomized Phase III clinical trials in ALK-positive NSCLC are currently underway to compare the activity of crizotinib to standard of care. Nevertheless, based on the impressive responses observed in Phase I/II trial, the Food and Drug Administration (FDA) approved crizotinib for treatment of ALK rearranged NSCLC, under its accelerated approval program, on August 26, 2011. The National Comprehensive Cancer network guidelines recommend the use of crizotinib as first line therapy for ALK-positive selected NSCLC patients (www.nccn.org).

Other patients affected by rare malignancies for which a clear involvement of ALK had been demonstrated in preclinical studies, were also enrolled in the trial with crizotinib. For at least two patients with ALK-positive ALCL treated at the recommended Phase II dose, signs of clinical benefit were seen within a remarkably short treatment period, with a PR and a CR achieved (Gambacorti-Passerini and Messa, 2011). Two patients with IMT were enrolled already in the dose escalation phase: for one of these, a rapid and sustained partial response was seen. The other patient had no response to crizotinib, but retrospective genetic analysis showed that this IMT tumor lacked ALK rearrangement (Butrynski et al., 2010).

http://www.frontiersin.org/Cancer_Molecular_Targets_and_Therapeutics/10.3389/fonc.2012.00017/full

Crizotinib (Xalkori,[1] Pfizer), is an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene1, receptor tyrosine kinase) inhibitor, approved for treatment of some non-small cell lung carcinoma (NSCLC) in the US and some other countries, and undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and children.[2]

Mechanism of action
Human anaplastic lymphoma kinase in complex with crizotinib. PDB 2xp2[3]

Crizotinib has an aminopyridine structure, and functions as a protein kinase inhibitor by competitive binding within the ATP-binding pocket of target kinases. About 4% of patients with non-small cell lung carcinoma have a chromosomal rearrangement that generates a fusion gene between EML4 ('echinoderm microtubule-associated protein-like 4') and ALK ('anaplastic lymphoma kinase'), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype. [4] The kinase activity of the fusion protein is also inhibited by crizotinib.[4] Patients with this gene fusion are typically younger non-smokers who do not have mutations in either the epidermal growth factor receptor gene (EGFR) or in the K-ras gene.[4][5] The number of new cases of ALK-fusion NSLC is about 9,000 per year in the U.S. and about 45,000 worldwide.[6][7]

ALK mutations are also thought to be important in driving the malignant phenotype in about 15% of cases of neuroblastoma, a rare form of peripheral nervous system cancer that occurs almost exclusively in very young children.[8]

Crizotinib also inhibits the c-Met/Hepatocyte growth factor receptor (HGFR) tyrosine kinase, which is involved in the oncogenesis of a number of other histological forms of malignant neoplasms.[9]

Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells.[9][10] Other studies suggest that crizotinib may also act via inhibition of angiogenesis in malignant tumors.[11]
Clinical trials

Crizotinib caused tumors to shrink or stabilize in 90% of 82 patients carrying the ALK fusion gene.[5][6] Tumors shrank at least 30% in 57% of people treated.[6] [12] Most had adenocarcinoma, and had never smoked or were former smokers.[5] They had undergone treatment with an average of three other drugs prior to receiving crizotinib, and only 10% were expected to respond to standard therapy.[5][13] They were given 250 mg crizotinib twice daily for a median duration of six months.[5] Approximately 50% of these patients suffered at least one side effect, such as nausea, vomiting, or diarrhea.[13] Some responses to crizotinib have lasted up to 15 months.[13]

A phase 3 trial, PROFILE 1007,[14] compares crizotinib to standard second line chemotherapy (pemetrexed or taxotere) in the treatment of ALK-positive NSCLC.[2][7][15] Additionally, a phase 2 trial, PROFILE 1005, studies patients meeting similar criteria who have received more than one line of prior chemotherapy.[7]

On August 26, 2011, the U.S. Food and Drug Administration approved crizotinib (Xalkori) to treat certain late-stage (locally advanced or metastatic) non-small cell lung cancers that express the abnormal anaplastic lymphoma kinase (ALK) gene.[1] Approval required a companion molecular test for the EML4-ALK fusion.

Crizotinib is also being tested in clinical trials of advanced disseminated anaplastic large-cell lymphoma,[9] and neuroblastoma.[16]

http://en.wikipedia.org/wiki/Crizotinib

http://www.drugs.com/mtm_esp/crizotinib.html

http://www.nlm.nih.gov/medlineplus/spanish/druginfo/meds/a612018-es.html

http://www.medscape.org/viewarticle/764663

http://cancergrace.org/lung/2010/06/09/alk-talk/

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