Epothilones as Natural Compounds for Novel Anticancer Drugs Development.

Epothilone is a natural 16-membered macrolide cytotoxic compound produced by the metabolism of the cellulose-degrading myxobacterium Sorangium cellulosum. This review summarizes results in the study of epothilones against cancer with preclinical results and clinical studies from 2010-2022. Epothilone have mechanisms of action similar to paclitaxel by inducing tubulin polymerization and apoptosis with low susceptibility to tumor resistance mechanisms. It is active against refractory tumors, being superior to paclitaxel in many respects. Since the discovery of epothilones, several derivatives have been synthesized, and most of them have failed in Phases II and III in clinical trials; however, ixabepilone and utidelone are currently used in clinical practice. There is robust evidence that triple-negative breast cancer (TNBC) treatment improves using ixabepilone plus capecitabine or utidelone in combination with capecitabine. In recent years innovative synthetic strategies resulted in the synthesis of new epothilone derivatives with improved activity against refractory tumors with better activities when compared to ixabepilone or taxol. These compounds together with specific delivery mechanisms could be developed in anti-cancer drugs.

Eficacia y seguridad de ixabepilona para el tratamiento de pacientes con cáncer de mama metastásico resistente a antraciclina, taxanos y capecitabina con estado funcional ECOG 0-1 / Efficacy and safety of ixabepilone for the treatment of patients with metastatic breast cancer resistant to anthracyclines, taxanes and capecitabine with ECOG performance status 0-1

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de ixabepilona, comparado con la mejor terapia de soporte, para el tratamiento de pacientes con cáncer de mama metastásico (CMM) resistente a antraciclinas, taxanos y capecitabina con estado funcional ECOG 0-1. El cáncer de mama es la neoplasia más frecuente en mujeres en todo el mundo. En Perú, el cáncer de mama es la tercera causa de muerte por cáncer, con una tasa de mortalidad estandarizada por edad de 9.1 muertes por cada 100,000 habitantes. El cáncer mama metastásico (CMM) es una condición incurable que ocurre cuando la enfermedad se ha diseminado más allá de la mama y los ganglios linfáticos ipsilaterales hacia otros órganos. Se estima que la tasa de sobrevida global (SG) en pacientes con CMM, hasta los 5 años, es de aproximadamente 27 % con una mediana de SG de dos a tres años. Sin embargo, la esperanza de vida es menor a 1 año en pacientes con CMM que ya han recibido tres líneas de quimioterápicos. Asimismo, el 62 % de las pacientes con CMM tienen afectación visceral (hígado, pulmón o pleura), lo que compromete el funcionamiento normal de los órganos y las pacientes pueden presentar crisis visceral. La quimioterapia, dentro de las terapias sistémicas, es la principal opción terapéutica para la mayoría de las pacientes con CMM. No obstante, en casos muy avanzados de la enfermedad (como el CMM) y/o en casos de resistencia a varias líneas de tratamiento, las opciones terapéuticas que se pueden ofrecer a estas pacientes son escasas. Actualmente, EsSalud dispone de agentes quimioterápicos como: antraciclinas (inhibidor de topoisomerasa II), taxanos (agente anti microtúbulo) y capecitabina (inhibidor de nucleósido metabólico) para el tratamiento de pacientes con CMM. No obstante, ciertos pacientes no responden favorablemente a estos tratamientos. Los especialistas sugieren que ixabepilona puede ser una alternativa de tratamiento para los pacientes con CMM resistente a otros agentes como: antraciclinas, taxanos y capecitabina. METODOLOGÍA: Se llevó a cabo una búsqueda de la literatura científica con el objetivo de identificar la mejor evidencia sobre la eficacia y seguridad de ixabepilona en pacientes con CMM resistente a antraciclinas, taxanos y capecitabina con estado funcional ECOG 0-1. La búsqueda sistemática se realizó en las principales bases de datos PubMed, The Cochrane Library y LILACS. Asimismo, se realizó una búsqueda manual dentro de las bases de datos pertenecientes a grupos que realizan evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC); incluyendo el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), el Scottish Medicines Consortium (SMC), la Scottish Intercollegiate Guidelines Network (SIGN), el Institute for Clinical and Economic Review (ICER), el Institut für Qualität und Wirtschaftlichkeit im Gesundheitswese (IQWiG), la Base Regional de Informes de evaluación de tecnologías en Salud de las Américas (BRISA), la Organización Mundial de la Salud (OMS), el Ministerio de Salud del Perú (MINSA) y el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI). Además, se realizó una búsqueda de GPC de las principales sociedades o instituciones especializadas en oncología como National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO) y American Society of Clinical Oncology (ASCO). Finalmente, se realizó una búsqueda manual en la página web de registro de EC de ClinicalTrials.gov del National Institutes of Health (https://clinicaltrials.gov/) para identificar EC en curso o de resultados que no hayan sido publicados aún. RESULTADOS: Se llevó a cabo una búsqueda de evidencia científica con respecto al uso de ixabepilona como tratamiento de pacientes con CMM resistente a antraciclinas, taxanos y capecitabina con estado funcional ECOG 0-1. CONCLUSIONES:  El presente dictamen tuvo como objetivo evaluar la mejor evidencia disponible hasta julio de 2021 sobre la eficacia y seguridad de ixabepilona como terapia para pacientes con CMM resistente a antraciclinas, taxanos y capecitabina con ECOG 0-1.  Luego de la búsqueda sistemática, se identificaron dos GPC elaboradas por la NCCN y por la ESO-ESMO y un ensayo clínico de fase II (NCT00080262). Sobre las GPC, la NCCN señala que la mayoría de pacientes serán candidatos a múltiples líneas de terapia sistémica en función de su estado funcional; sin embargo, no especifica el número de líneas tratamiento a brindar. Dentro estos tratamientos señalan algunos como preferentes (antraciclinas, taxanos, capecitabina, gemcitabina y vinorelbina) y a otros como no preferentes (otros quimioterápicos e ixabepilona). La NCCN y la ESO-ESMO recomiendan la terapia paliativa. La NCCN recomienda que se considere no continuar con la terapia sistémica citotóxica y ofrecer la terapia paliativa en paciente con CMM que ha recibido varias líneas de quimioterápicos. La ESO-ESMO recomienda la terapia paliativa en pacientes con CMM cuyo tratamiento activo (e.g. quimioterapia) ya no sea capaz de controlar la enfermedad metastásica y la toxicidad supere los beneficios. El ensayo clínico de fase II, sin grupo control, evaluó el efecto de ixabepilona en la SG y la seguridad en pacientes con CMM resistente a antraciclina, taxanos y capecitabina. Debido al sesgo de reporte de resultados y, principalmente, la falta de grupo control, no se puede establecer una relación causal entre los resultados observados y el tratamiento con ixabepilona. Por lo tanto, no se puede determinar la eficacia comparativa entre ixabepilona y la mejor terapia de soporte que consiste en continuar con el uso de quimioterápicos y brindar cuidado paliativo. La incidencia de EA de grado 4 (34 %), el 11 % de pacientes que descontinuaron el tratamiento y la una muerte asociada al uso de ixabepilona, reportados en el EC fase II, y que fueron el motivo por que cual la EMA no aprobó su uso, sugieren que el perfil de seguridad de ixabepilona no sería favorable. Las evaluaciones de ixabepilona por parte de la EMA y la DIGEMID, basados en el EC fase II, concluyeron que los riesgos de ixabepilona superan sus potenciales beneficios en el tratamiento de pacientes con CMM. Por lo tanto, para estas instituciones tampoco sería seguro el uso de ixabepilona en el subgrupo de pacientes con CMM resistente a antraciclinas, taxanos y capecitabina.  Por lo expuesto, el IETSI no aprueba el uso de ixabepilona para el tratamiento de paciente con cáncer de mama metastásico resistente a antraciclinas, taxanos y capecitabina con estado funcional ECOG 0-1.

Eficacia y seguridad de ixabepilona en el tratamiento médico oncológico del cáncer de mama triple negativo resistente a antraciclinas y taxanos / Efficacy and safety of ixabepilone in the medical oncological treatment of triple negative breast cancer resistant to anthracyclines and taxanes

INTRODUÇÃO: El cáncer de mama es una enfermedad con una alta incidencia y mortalidad a nivel mundial, latinoamericano y en Perú. Se describen cuatro subtipos de cáncer de mama según la expresión o no de cuatro marcadores (receptor de estrógeno, RE; receptor de progesterona, RP; HER2 y Ki67): Luminal, HER2 y triple negativo; representando este último un 21% de los casos según un estudio llevado a cabo en población institucional. - La ixabepilona es un antineoplásico perteneciente al grupo de las epotilonas que se encargan de estabilizar los microtúbulos causando una muerte celular por apoptosis. Es un medicamento que ha sido evaluado en estudios de fase II obteniendo resultados favorables en pacientes con cáncer de mama avanzando y además se han realizado estudios de fase III que avalan su uso en pacientes con cáncer de mama avanzado que han progresado a terapias con antraciclinas y taxanos. METODOLOGÍA: Se decidió realizar un informe de ETS que permita mostrar la eficacia y seguridad de la ixabepilona con capecitabina comparada con capecitabina sola para el tratamiento oncológico de pacientes con cáncer de mama triple negativo resistentes a antraciclinas y taxanos. Se encontró que una GPC internacional (NCCN) avala el uso de ixabepilona en pacientes con cáncer de mama avanzado y el documento institucional también menciona estudios que avalan su utilidad en estos pacientes; sin embargo, la guía de ESMO no menciona su uso lo cual se debe a que EMA no aprobó su incorporación en Europa y que disponen de otras alternativas como eribulina. Además, se encontraron 04 ETS o informes relacionados en los cuales se ha reportado evidencia sobre el uso de ixabepilona en pacientes con cáncer de mama avanzado. DISCUSIÓN: La discusión con el panel se llevó a cabo durante dos sesiones en las cuales se expuso la PICO, la estrategia de búsqueda, las evidencias con respecto a la guías de práctica clínica, informes de evaluación de tecnologías sanitarias y documentos relacionados. Además, los análisis comparativos de eficacia y seguridad así como los análisis de costos de los diferentes medicamentos disponibles para el tratamiento de cáncer de mama avanzado triple negativo. En la primera sesión se comentó que ixabepilona es un tratamiento que se ha estado usando a nivel institucional en monoterapia para el tratamiento de pacientes con cáncer de mama triple negativo localmente avanzado o metastasico que hayan recibido terapia previa incluyendo una antraciclina, un taxano y/o capecitabina. Los casos se aprueban a través de junta médica y se realiza una vigilancia periódica. A la fecha 18 pacientes han recibido el tratamiento. Además, un integrante del panel manifestó que está de acuerdo con la propuesta brindada por el informe de Instituto de Cáncer de Argentina que especifica "No se sugiere el uso rutinario de Ixabepilona como tratamiento en pacientes con CMM RH positivos HER2 negativos, ECOG 0-1 y enfermedad evaluable salvo en pacientes seleccionadas: resistentes a antraciclinas/taxanos sin neuropatía residual significativa, con enfermedad visceral sintomática. (Condicional, moderada)". Se comentó que se tiene conocimiento de los pacientes que están recibiendo el tratamiento y que es un grupo que presentan bajo riesgo de presentar neutropenia o neuropatía periférica. No ha habido reportes adversos serios hasta el momento a nivel institucional con respecto al uso de este medicamento. Se consultó si es que se disponía de otras terapias que puedan ser comparadas con ixabepilona con respecto a eficacia y seguridad de los pacientes con cáncer de mama triple negativo que progresan a antraciclinas y taxanos. Es necesario conocer que estudios existen y poder concluir si es que ixabepilona sería la mejor intervención farmacológica disponible para estos casos específicos de paciente o existiría alguna otra que esté disponible a nivel nacional y que pueda usarse. Durante segunda reunión se mencionó que a nivel internacional se tiene la disponibilidad del medicamento eribulina que ha reportado mejores resultados con respecto a otros tratamientos en el cáncer de mama avanzado triple negativo a nivel nacional pero no se cuenta con disponibilidad de este medicamento a nivel nacional además que los costos son muy elevados por ello se mencionó que es una necesidad que se continúe con la disponibilidad de este medicamento. Además, en base a lo reportado a nivel institucional se mencionó que es necesario ser más específico en la indicación y los pacientes a los cuales se les va a prescribir el medicamento. Además, ppdría considerarse que Ixabepilona asociado a Capecitabina podría ser utilizado en población mejor seleccionada: ECOG 0 ­ 1, expuestos a antraciclinas y taxanos, que no hayan sido expuesto a capecitabina, donde se haya descartado metástasis cerebral previa al inicio del tratamiento y en pacientes con sospecha de mutación BRCA ofrecerles terapia con sales de platino. Con respecto a la evidencia en supervivencia global, supervivencia libre de progresión, tasa de respuesta objetiva de otras intervenciones farmacológicas se encuentran valores similares a los reportados por ixabepilona. Con respecto al tratamiento brindado a los 11 pacientes a nivel institucional no se ha podido establecer beneficios: tres de 11 pacientes han fallecido, no se ha documentado algún tipo de respuesta parcial. Por otro lado, se mencionó que en base a lo reportado es difícil proponer continuar con la adquisición del medicamento ya que no ha demostrado superioridad en supervivencia global y que no se cuenta con estudios de evaluaciones económicas o análisis de impacto presupuestario que avalen contar con el medicamento además que el costo adicional que implica la prescripción del medicamento es elevado. Se mencionó que al actualmente el SIS no viene cubriendo todos los medicamentos no PNUME, por lo que solicita se considere un tratamiento alterno a Ixabepilona que si se encuentre disponible en la lista PNUME. CONCLUSIONES: En el Instituto Nacional de Enfermedades Neoplásicas (INEN) en base a la información del departamento de oncología médica se han proyectado de maneral anual un promedio de 18 a 35 casos de pacientes con cáncer de mama triple negativo resistentes a antraciclinas y taxanos. Se realizó una búsqueda sistemática y una búsqueda dirigida de la evidencia para evaluar la eficacia y seguridad del uso de ixabepilona con capecitabina comparado con capecitabina sola para el tratamiento médico oncológico de pacientes con cáncer de mama triple negativo resistente a antraciclinas y taxanos. Se incluyó 02 guías de práctica clínica internacionales y un documento técnico institucional, 05 evaluaciones de tecnologías sanitarias o informes relacionados y un estudio de análisis combinado de dos ensayos clínicos que analiza a ixabepilona en monodroga comparado con la combinación de ixabepilona con capecitabina. Adicionalmente, se han incluido 05 estudios de otras opciones terapéuticas disponibles para el tratamiento de cáncer de mama avanzado triple negativo. En las GPC; en una se menciona el uso de ixabepilona en el manejo de cáncer de mama avanzado, en otra GPC no se establece una recomendación pero si colocan otras opciones como capecitabina, gemcitabina, etc; y en el documento institucional se la menciona pero no se especifican recomendaciones dentro del grupo de cáncer de mama triple negativo resistente a antraciclinas y taxanos. n las 04 ETS. Se menciona que en los países donde está permitida su comercialización, su uso se permite para pacientes con características específicas siendo la ETS Argentina la que emite una recomendación débil en contra sobre su uso y reserva el uso de ixabepilona en pacientes con cáncer de mama avanzado con características específicas de manera excepcional. El estudio de Rugo que combina los datos reportados en 02 ensayos clínicos de fase III ha encontrado un aumento en la supervivencia libre de progresión en el grupo de ixabepilona más capecitabina y duplicación en la tasa de respuesta objetivo; sin embargo, no se encontró aumento en el desenlace crítico supervivencia global ni en calidad de vida, encontrándose también un aumento en la frecuencia de eventos adversos relacionados a toxicidad por la terapia combina, neutropenia y neuropatías periféricas. La calidad de evidencia global fue moderada. Con respecto a lo evidenciado por otros medicamentos en pacientes con cáncer de mama avanzado triple negativo resistentes a antraciclinas y/o taxanos no se ha encontrado alguno que logre impactar en supervivencia global, se reportan si otros desenlaces importantes con valores similares a los reportados por el medicamento ixabepilona. El medicamento está disponible a nivel nacional y ha sido aprobado tanto por FDA, y DIGEMID para su uso en pacientes con cáncer de mama metastásico. No está aprobado por EMA. Con respecto al costo, éste podría exceder en 30 mil nuevos soles comparado al resto de alternativas disponibles en la lista PNUME. Se estima que por cada paciente se requiere aproximadamente 8 UIT. Finalmente, el panel multidisciplinario debido a la evidencia mostrada y la experiencia institucional, no tiene como justificar la continuidad de la terapia brindando opinión en contra de la cobertura del medicamento Ixabepilona. Se elevará informe y acta a Comité Farmacoterapéutico sobre los acuerdos de reunión.

Physical Activity, Weight, and Outcomes in Patients Receiving Chemotherapy for Metastatic Breast Cancer (C40502/Alliance).

Background: Obesity and inactivity are associated with increased risk of cancer-related and overall mortality in breast cancer, but there are few data in metastatic disease. Methods: Cancer and Leukemia Group B 40502 was a randomized trial of first-line taxane-based chemotherapy for patients with metastatic breast cancer. Height and weight were collected at enrollment. After 299 patients enrolled, the study was amended to assess recreational physical activity (PA) at enrollment using the Nurses' Health Study Exercise Questionnaire. Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using stratified Cox modeling (strata included hormone receptor status, prior taxane, bevacizumab use, and treatment arm). All statistical tests were 2-sided. Results: A total of 799 patients were enrolled, and at the time of data lock, median follow-up was 60 months. At enrollment, median age was 56.7 years, 73.1% of participants had hormone receptor-positive cancers, 42.6% had obesity, and 47.6% engaged in less than 3 metabolic equivalents of task (MET) hours of PA per week (<1 hour of moderate PA). Neither baseline body mass index nor PA was statistically significantly associated with PFS or OS, although there was a marginally statistically significant increase in PFS (hazard ratio = 0.83, 95% confidence interval = 0.79 to 1.02; P = .08) and OS (hazard ratio = 0.81, 95% confidence interval = 0.65 to 1.02; P = .07) in patients who reported PA greater than 9 MET hours per week vs 0-9 MET hours per week. Conclusions: In a trial of first-line chemotherapy for metastatic breast cancer, rates of obesity and inactivity were high. There was no statistically significant relationship between body mass index and outcomes. More information is needed regarding the relationship between PA and outcomes.

Cytotoxic effect of targeted biodegradable epothilone B and rapamycin co-loaded nanocarriers on breast cancer cells.

The new therapeutic solutions for breast cancer treatment are needed, for example, combined therapy consisted of several drugs that characterize different mechanisms of action and modern drug delivery systems. Therefore, we used combination of epothilone B (EpoB) and rapamycin (Rap) to analyze the cytotoxic effect against breast cancer cells (MCF-7; MDA-MB-231). Also, the effect of drugs co-delivered in bioresorbable micelles functionalized with biotin (PLA-PEG-BIO; poly(lactide)-co-poly(ethylene glycol)-biotin) was studied. The comparison of effects of the mixture of free drugs and the micelles co-loaded with EpoB and Rap revealed a significant decrease in the cell metabolic activity and survival. Moreover, the dual drug-loaded PLA-PEG-BIO micelles enhanced the cytotoxicity of EpoB and Rap against the tested cells as compared with the free drugs. The blank PLA-PEG-BIO micelles did not affect the tested cells. We expect that mixture of EpoB and Rap may be promising in breast cancer treatment and PLA-PEG-BIO micelles as carrier of these two drugs can be applicable for successful targeted delivery.

Microtubule Stabilization Promotes Microcirculation Reconstruction After Spinal Cord Injury.

Spinal cord microcirculation plays an important role in maintaining the function of spinal cord neurons and other cells. Previous studies have largely focused on the ability of microtubule stabilization to inhibit the fibroblast migration and promote axon regeneration after spinal cord injury (SCI). However, the effect of microtubule stabilization treatment on microcirculation reconstruction after SCI remains unclear. By using immunofluorescence, we found that microtubule stabilization treatment improved microcirculation reconstruction via increasing the number of microvessels, pericytes, and the perfused microvessels after SCI. To clarify the underlying mechanisms, rat brain microvascular endothelial cells and pericytes were subjected to glucose oxygen deprivation. By using flow cytometry and western blotting, we found that microtubule stabilization treatment inhibited apoptosis and migration of endothelial cells and pericytes but promoted proliferation and survival of endothelial cells and pericytes through upregulated expression of vascular endothelial growth factor A (VEGFA), VEGF receptor 2, platelet-derived growth factor-B (PDGFB), PDGF receptor ß, and angiopoietin-1 after SCI. Taken together, this study provides evidence for the mechanisms underlying the promotion of microcirculation reconstruction after SCI by microtubule stabilization treatment. Importantly, this study suggests the potential of microtubule stabilization as a therapeutic target to reduce microcirculation dysfunction after SCI in the clinic.

Stabilization of microtubules improves cognitive functions and axonal transport of mitochondria in Alzheimer's disease model mice.

One major pathological process in Alzheimer's disease is mediated by hyperphosphorylated tau, which includes altered microtubules (MTs) and functions associated with tau. A potential way to compensate for altered MT function is to use an MT stabilizer, such as epothilone D (EpoD). Previous studies have demonstrated improved cognitive functions and axonal transport by EpoD in tau-mutation mice. Here, we demonstrated that extended EpoD treatment also has beneficial effects on APP/PS1 double-transgenic mice, improving their motor and spatial memory, increasing key synaptic protein levels, while not affecting amyloid plaque density or level of tau phosphorylation. Interestingly, EpoD appears to improve the retrieval of formed memories. We also observed improved axonal transport of mitochondria in cultured neurons from APP/PS1 mice. In addition, higher level of perineuronal nets are found in APP/PS1 mice injected with EpoD, suggesting potential contributions of increased inhibition. Our results suggest potential therapeutic value of EpoD in treating Alzheimer's disease.

The pathologic outcomes and efficacy of epothilone treatment following traumatic brain injury is determined by age.

Traumatic brain injury (TBI) can affect individuals at any age, with the potential of causing lasting neurologic consequences. The lack of effective therapeutic solutions and recommendations for patients that acquire a TBI can be attributed, at least in part, to an inability to confidently predict long-term outcomes following TBI, and how the response of the brain differs across the life span. The purpose of this study was to determine how age specifically affects TBI outcomes in a preclinical model. Male Thy1-YFPH mice, that express yellow fluorescent protein in the cytosol of a subset of Layer V pyramidal neurons in the neocortex, were subjected to a lateral fluid percussion injury over the right parietal cortex at distinct time points throughout the life span (1.5, 3, and 12 months of age). We found that the degree of neuronal injury, astrogliosis, and microglial activation differed depending on the age of the animal when the injury occurred. Furthermore, age affected the initial injury response and how it resolved over time. Using the microtubule stabilizing agent Epothilone D, to potentially protect against these pathologic outcomes, we found that the neuronal response was different depending on age. This study clearly shows that age must be taken into account in neurologic studies and preclinical trials involving TBI, and that future therapeutic interventions must be tailored to age.

Epothilone B prevents lipopolysaccharide-induced inflammatory osteolysis through suppressing osteoclastogenesis via STAT3 signaling pathway.

Inflammatory osteolysis is a common osteolytic specificity that occurs during infectious orthopaedic surgery and is characterized by an imbalance in bone homeostasis due to excessive osteoclast bone resorption activity. Epothilone B (Epo B) induced α-tubulin polymerization and enhanced microtubule stability, which also played an essential role in anti-inflammatory effect on the regulation of many diseases. However, its effects on skeletal system have rarely been investigated. Our study demonstrated that Epo B inhibited osteoclastogenesis in vitro and prevented inflammatory osteolysis in vivo. Further analysis showed that Epo B also markedly induced mature osteoclasts apoptosis during osteoclastogenesis. Mechanistically, Epo B directly suppressed osteoclastogenesis by the inhibitory regulation of the phosphorylation and activation of PI3K/Akt/STAT3 signaling directly, and the suppressive regulation of the CD9/gp130/STAT3 signaling pathway indirectly. The negative regulatory effect on STAT3 signaling further restrained the translocation of NF-κB p65 and NFATc1 from the cytosol to the nuclei during RANKL stimulation. Additionally, the expression of osteoclast specific genes was also significantly attenuated during osteoclast fusion and differentiation. Taken together, these findings illustrated that Epo B protected against LPS-induced bone destruction through inhibiting osteoclastogenesis via regulating the STAT3 dependent signaling pathway.

Cost-effectiveness analysis of utidelone plus capecitabine for metastatic breast cancer in China.

Objective: To estimate the cost-effectiveness of utidelone plus capecitabine therapy compared to capecitabine alone in patients with metastatic breast cancer (MBC) resistant to anthracyclines and taxanes treatment in the Chinese context and provide a reference for the marketing of utidelone in China. Methods: A Markov model was developed based on the NCT02253459 clinical trial to simulate the clinical course of patients with metastatic breast cancer who had received taxanes and anthracycline therapy. The quality-adjusted life years (QALYs) and Incremental Cost Effectiveness Ratio (ICER) were then analyzed to evaluate the benefits. Two-parametric Weibull distribution was conducted to fit PFS and OS curves by using R. Sensitivity analyses were performed to evaluate the stability of the model designed. Results: The addition of utidelone increased the cost and QALYs by $13,370.25 and 0.1961, respectively, resulting in an increased ICER of $68,180.78 per QALY. The most sensitive influential parameter on ICER was the price of utidelone. At the threshold of willingness-to-pay (WTP) of $24,380 (3 per capita GDP of China), the cost of utidelone per 30 mg of less than $18.5, $33.7, and greater than $48.8 resulted in a 100%, 50%, and 0% possibility of cost-effectiveness, respectively. The addition of utidelone was not cost-effective when it was $115.4 per 30 mg-the price of its analog paclitaxel. In consideration of varied economics levels across China, cost-effectiveness could be achieved with the price of utidelone ranging from $5.2 to $35.9. Limitations: The survival curves extended beyond the follow-up time horizon, of which data were generated not from the real analyses but from our established two-parameter Weibull survival model. Conclusion: It is recommended that the price of utidelone would be less than $18.5 per 30 mg in order to obtain cost-effectiveness for metastatic breast cancer patients resistant to anthracyclines and taxanes treatment in China.

Dynamic Microtubules in Alzheimer's Disease: Association with Dendritic Spine Pathology.

Alzheimer's disease (AD) is the most common incurable neurodegenerative disorder that affects the processes of memory formation and storage. The loss of dendritic spines and alteration in their morphology in AD correlate with the extent of patient's cognitive decline. Tubulin had been believed to be restricted to dendritic shafts, until recent studies demonstrated that dynamically growing tubulin microtubules enter dendritic spines and promote their maturation. Abnormalities of tubulin cytoskeleton may contribute to the process of dendritic spine shape alteration and their subsequent loss in AD. In this review, association between tubulin cytoskeleton dynamics and dendritic spine morphology is discussed in the context of dendritic spine alterations in AD. Potential implications of these findings for the development of AD therapy are proposed.

UCBG 2-08: 5-year efficacy results from the UNICANCER-PACS08 randomised phase III trial of adjuvant treatment with FEC100 and then either docetaxel or ixabepilone in patients with early-stage, poor prognosis breast cancer.

PURPOSE: UNICANCER-PACS08 compared adjuvant FEC (5-FU; epirubicin; cyclophosphamide) then docetaxel to FEC then ixabepilone in poor prognosis early breast cancer (BC). We evaluated whether replacing docetaxel with ixabepilone would increase 5-year disease-free survival (DFS). PATIENTS AND METHODS: Triple-negative breast cancer (TNBC) or oestrogen receptor (ER)+/progesterone receptor (PR)-/HER2- BC patients were randomised to receive standard FEC (3 cycles) followed by 3 cycles of either docetaxel (100 mg/m2) or ixabepilone (40 mg/m2). Radiotherapy was mandatory after conservative surgery; ER+ patients received endocrine therapy. RESULTS: Seven hundred sixty-two patients were enrolled between October 2007 and September 2010. Baseline characteristics were balanced between arms. Median follow-up was 66.7 months. Median DFS was not reached; 5-year DFS rate was 76% with docetaxel and 79% with ixabepilone (hazard ratio [HR] = 0.80; 95% confidence interval [CI] = 0.58-1.10; p = 0.175). Median overall survival (OS) was not reached; 5-year OS rate was 86% versus 84% (HR = 0.97; 95% CI = 0.66-1.42; p = 0.897). TNBC patients treated with ixabepilone had a 23% lower risk of relapse compared to docetaxel (HR for DFS = 0.77; 95% CI = 0.53-1.11; p = 0.168). DFS was longer with ixabepilone than docetaxel in patients with grade II-III lymphocytic infiltration (HR = 0.55; 95% CI = 0.29-1.05; p = 0.063). All patients experienced ≥1 adverse events (AEs): 75% reported grade III-IV AEs and two (<1%) had grade V AEs (both with neutropenia and infection receiving ixabepilone). CONCLUSION: After adjuvant FEC, ixabepilone was comparable to docetaxel for treating poor prognosis early BC patients. The benefit of ixabepilone in subgroups (patients with TNBC and grade II-III lymphocytic infiltration) requires further evaluation.

Synthesis and Activity of Epothilone D.

Epothilones are a class of macrolide compounds. Their activities of tubulin polymerization and microtubule depolymerization inhibition like paclitaxel make them a new generation of antimitotic drugs. The mechanism of action is similar to that of paclitaxel, which can bind to tubulin and cause cancer cells to fail to undergo mitosis, thereby causing apoptosis in cancer cells. Epothilone is superior to paclitaxel in anti-tumor spectrum, anti-tumor activity, safety, water solubility and synthetic methods. It is expected to develop into a more effective anti-tumor drug than paclitaxel. Herein, the synthesis methods and activity of epothilone D were summarized and analyzed.

Stably maintained microtubules protect dopamine neurons and alleviate depression-like behavior after intracerebral hemorrhage.

Mesolimbic dopamine (DA) system lesion plays a key role in the pathophysiology of depression, and our previous study demonstrated that reduced microtubule (MT) stability aggravated nigrostriatal pathway impairment after intracerebral hemorrhage (ICH). This study aimed to further investigate the occurrence regularity of depression-like behavior after ICH and determine whether maintaining MT stabilization could protect DA neurons in ventral tegmental area (VTA) and alleviate depression-like behavior after ICH. An intrastriatal injection of 20 µl of autologous blood or MT depolymerization reagent nocodazole (Noco) was used to mimic the pathology of ICH model in mice. The concentration of DA, number of DA neurons and acetylated α-tubulin (a marker for stable MT) in VTA were checked, and depression-related behavior tests were performed after ICH. A MT-stabilizing agent, epothilone B (EpoB), was administered to explore the effects of MT stabilization on DA neurons and depression-like behavior after ICH. The results showed that obvious depression-like behavior occurred at 7, 14, and 28 days (P < 0.01) after ICH. These time-points were related to significant decreases in the concentration of DA (P < 0.01) and number of DA neurons (P < 0.01) in VTA. Moreover, The decrease of acetylated α-tubulin expression after ICH and Noco injection contributed to DA neurons' impairment in VTA, and Noco injecton also aggravate ICH-induced depression-like behaviors and DA neurons' injury. Furthermore, EpoB treatment significantly ameliorated ICH and Noco-induced depression-like behaviors (P < 0.05) and increased the concentration of DA (P < 0.05) and number of DA neurons (P < 0.05) in VTA by increasing the level of acetylated α-tubulin. The results indicate that EpoB can protect DA neurons by enhancing MT stability, and alleviate post-ICH depressive behaviors. This MT-targeted therapeutic strategy shows promise as a bench-to-bedside translational method for treating depression after ICH.

Therapeutic potential of patupilone in epithelial ovarian cancer and future directions.

Ovarian cancer is the most lethal gynecologic malignancy worldwide with extremely poor patient prognosis. Elucidation of the detailed mechanisms of action of drugs targeting this cancer type is necessary to optimize treatment efficacy. Epothilones, a new class of microtubule-stabilizing anticancer drugs, show strong cytotoxic properties in vitro and in vivo and are additionally effective in taxane-resistant cells. In this report, we focus on inhibitors of microtubule depolymerization, taxanes, and the novel antimicrotubule agents, epothilones. Current knowledge regarding the effects of epothilone B on ovarian tumor cell metabolism is reviewed, along with recent advances in therapeutic strategies, such as novel agents and biologic drug combinations containing epothilone that target aberrant pathways in ovarian cancer.

Continuous low-dose infusion of patupilone increases the therapeutic index in mouse and rat tumour models.

Patupilone is a microtubule-targeted cytotoxic agent with clinical efficacy, but causes diarrhoea in more than 80% of patients. The efficacy and tolerability of patupilone delivered continuously by subcutaneous (s.c.) mini-pumps [(mini-pump dose (MPD)] or by intravenous bolus administration [intravenous bolus dose (IVBD)] were compared preclinically to determine whether the therapeutic index could be improved. The antiproliferative potency in vitro of patupilone was determined by measuring total cell protein. Tumours were grown s.c. in rats (A15) or nude mice (KB31, KB8511) or intracranially in nude mice (NCI-H460-Luc). Efficacy was monitored by measuring tumour volumes, bioluminescence or survival. Toxicity was monitored by body weight and/or diarrhoea. Total drug levels in blood, plasma, tissues or dialysates were quantified ex-vivo by liquid chromatography-mass spectroscopy/mass spectroscopy. Patupilone was potent in vitro with GI50s of 0.24-0.28 nmol/l and GI90s of 0.46-1.64 nmol/l. In rats, a single IVBD of patupilone dose dependently inhibited the growth of A15 tumours, but also caused dose-dependent body weight loss and diarrhoea, whereas MPD achieved similar efficacy, but no toxicity. In mice, MPD showed efficacy similar to that of IVBD against KB31 and KB8511 tumours, but with reduced toxicity. In a mouse intracranial tumour model, IVBD was more efficacious than MPD, consistent with patupilone concentrations in the brain. MPD provided constant plasma levels, whereas IVBD had very high C0/Cmin ratios of 70-280 (rat) or 8000 (mouse) over the dosing cycle. Overall, the correlation of plasma and tumour levels with response indicated that a Cave of at least GI90 led to tumour stasis. Continuous low concentrations of patupilone by MPD increased the therapeutic index in s.c. rodent tumour models compared with IVBD by maintaining efficacy, but reducing toxicity.

Stabilization of microtubules restores barrier function after cytokine-induced defects in reconstructed human epidermis.

BACKGROUND: A variety of human skin disorders is characterized by defects in the epidermal barrier, leading to dehydration, itchiness, and rashes. Previously published literature suggests that microtubule stabilization at the cortex of differentiating keratinocytes is necessary for the formation of the epidermal barrier. OBJECTIVES: We tested whether stabilization of microtubules with paclitaxel or epothilone B can repair barrier defects that were experimentally induced in three-dimensional culture models of epidermis. METHODS: We established two models of defective epidermis in vitro, using three-dimensional cultures of primary human keratinocytes on filter supports: immature reconstructed human epidermis (RHE), and RHE that was compromised by treatment with inflammatory cytokines, the latter mimicking defects seen in atopic dermatitis. RESULTS: Both paclitaxel and epothilone B promoted keratinocyte differentiation, accumulation of junctional proteins at the cell cortex, and the early appearance of lamellar bodies in immature RHE, whereas destabilization of microtubules by nocodazole had the reverse effect. Moreover, stabilization of microtubules rescued the barrier after cytokine treatment. The rescued barrier function correlated with the restoration of filaggrin and loricrin protein levels, the cortical accumulation of junctional proteins (E-cadherin, ß-catenin, and claudin-1), and with the secretion of lamellar bodies. CONCLUSIONS: Our data suggest that the microtubule network is important for the formation of the epidermis, and that stabilization of microtubules promotes barrier formation. Microtubule stabilization may support regeneration of damaged skin, by restoring or improving the barrier.

Epothilone B Speeds Corneal Nerve Regrowth and Functional Recovery through Microtubule Stabilization and Increased Nerve Beading.

The successful restoration of corneal innervation and function after a corneal injury is a clinically challenging issue. Structural and functional recovery after a nerve injury involves a complex series of steps in which microtubules play a key role. The aim of the current study was to investigate the effects of epothilone B (EpoB), a microtubule-stabilizing agent, on corneal innervation and the functional recovery of the corneal nerve in mice after corneal epithelial abrasion. The pretreatment of mice with EpoB has a remarkable effect on the stabilization of beta-III tubulin, as demonstrated by substantial increases in the visualization of beta-III tubulin, nerve beading, corneal reinnervation, and reaction to stimuli. Furthermore, a pharmacokinetic analysis showed that EpoB remains at a high concentration in the cornea and the trigeminal ganglion for at least 6 days after administration. In addition, the administration of EpoB at 24 hours after corneal abrasion has a marked therapeutic effect on nerve regrowth and functional recovery. In conclusion, EpoB treatment may have therapeutic utility for improving corneal reinnervation and restoring sensitivity following corneal injury.

Systemic epothilone D improves hindlimb function after spinal cord contusion injury in rats.

Following a spinal cord injury (SCI) a growth aversive environment forms, consisting of a fibroglial scar and inhibitory factors, further restricting the already low intrinsic growth potential of injured adult central nervous system (CNS) neurons. Previous studies have shown that local administration of the microtubule-stabilizing drug paclitaxel or epothilone B (Epo B) reduce fibrotic scar formation and axonal dieback as well as induce axonal growth/sprouting after SCI. Likewise, systemic administration of Epo B promoted functional recovery. In this study, we investigated the effects of epothilone D (Epo D), an analog of Epo B with a possible greater therapeutic index, on fibrotic scarring, axonal sprouting and functional recovery after SCI. Delayed systemic administration of Epo D after a moderate contusion injury (150 kDyn) in female Fischer 344 rats resulted in a reduced number of footfalls when crossing a horizontal ladder at 4 and 8 weeks post-injury. Hindlimb motor function assessed with the BBB open field locomotor rating scale and Catwalk gait analysis were not significantly altered. Moreover, formation of laminin positive fibrotic scar tissue and 5-HT positive serotonergic fiber length caudal to the lesion site were not altered after treatment with Epo D. These findings recapitulate a functional benefit after systemic administration of a microtubule-stabilizing drug in rat contusion SCI.

Ixabepilone and Carboplatin for Hormone Receptor Positive/HER2-neu Negative and Triple Negative Metastatic Breast Cancer.

BACKGROUND: Hormonal therapies and single-agent sequential chemotherapeutic regimens are the standards of care for HER2- metastatic breast cancer (MBC). However, treating patients with hormone-refractory and triple negative (TN) MBC remains challenging. We report the results of combined ixabepilone and carboplatin in a single-arm phase II trial. PATIENTS AND METHODS: In the present prospective analysis of hormone receptor-positive (HR+)/HER2- and TN MBC cohorts, patients could have received 0 to 2 chemotherapy regimens for MBC before enrollment. All patients received ixabepilone 20 mg/m2 and carboplatin (area under the curve, 2.5) on days 1 and 8 every 21 days. The primary endpoint was the objective response rate (ORR). The secondary objectives included progression-free survival (PFS), clinical benefit rate (CBR), overall survival (OS), and toxicity. RESULTS: We enrolled 54 HR+ and 49 TN patients (median, 1 previous chemotherapy regimen for metastatic disease; most in addition to adjuvant chemotherapy). The ORR was 34% and 30.4% for the HR+ and TN patients, respectively, with a corresponding CBR of 56.6% and 41.3%. The ORRs were similar in taxane-pretreated patients (ORR, 31.4% and 28.6% for HR+ and TN patients, respectively). The median OS was 17.9 months for HR+ patients and 12.5 months for TN patients. The median PFS was similar for both groups at 7.6 months. Grade 3/4 nonhematologic toxicities included neuropathy (9%) and fatigue (8%). Nine patients developed grade 3/4 neuropathy, 7 of whom had received previous taxane treatment. CONCLUSION: Ixabepilone plus carboplatin is active even in later-line HR+ and TN disease. Toxicities were manageable without cumulative myelosuppression. This combination is a reasonable option for those patients with MBC who require combination chemotherapy.