PM1183 sigue el mismo camino que el Yondelis .
Bolsamania , martes, 8 abril 2014, 11:34 .
Los Analistas de Ahorro Corporación valoran hoy como “ Muy Positivo ” el anuncio de ayer de que la Food and Drug Administration (FDA) ha aceptado la propuesta de PharmaMar sobre el proceso de producción del PM1183, un agente en desarrollo clínico para el tratamiento de tumores sólidos y hematológicos .
Esta Aprobación es un paso que permite avanzar en la evolución clínica del fármaco, que ha culminado los ensayos clínicos de la fase II-b .
Es considerado como la segunda generación de Yondelis, y esperamos que, a corto-medio plazo, se anuncie la venta de la licencia a un tercero, como ocurriese en su momento con Yondelis y J&J” .
Para ello se utilizaron ratones que portaban diferentes tumores (NSCLC, gástrico, de páncreas o colon) obtenidos de pacientes, y que recibieron tratamiento con PM060184.
A continuación se determinó el efecto antitumoral del tratamiento y así, se demostró una reducción del tamaño tumoral muy importante alcanzándose, en algunos casos (NSCLC o gástrico) la desaparición completa del tumor implantado.
**********************************************
Background:
PM060184 is a synthetic marine-derived compound originally isolated from the marine sponge Lithoplocamia lithistoides. PM060184 induces disorganization and disruption of the microtubule network as well as aberrant mitotic spindle multipolarization and chromosome missegregation. These effects give rise to prometaphase arrest and formation of multinucleated cells. Then, cells enter to caspase-driven apoptosis or are arrested in a pseudo-senescent state. PM060184 is currently under evaluation in Phase I clinical studies in patients with advanced cancer diseases.
Material and Methods:
Athymic female nu/nu mice were subcutaneously implanted with different patient-derived tumors: NSCLC (N=4)), pancreas (N=5), colon (N=4) and gastric (N=2). Tumor (ca. 300 mm3) bearing animals (N=6-10/group) were randomly allocated to receive PM060184 (16 mg/kg) or placebo. Treatments were administered weekly for 5 consecutive weeks. Antitumor effect was calculated using ΔT/ΔC (%), defined as a percentage of the change in tumor size for treated (T) and placebo (C) groups during the placebo-treated survival time (D). Complete tumor regression (CR) was defined when tumor volume < 63 mm3 for 2 or more consecutive measurements.
Results:
The treatment with PM060184 produced lowest ΔT/ΔC values summarized as follows:
Tumor Minimal ΔT/ΔC (%) on Day :
NSCLC Pulm-005 2.2 32
Pulm 009 20.4 14
Pulm-016 0.0 45
Pulm-021 14.7 38
Pancreas Panc-215 37.3 35
Panc-265 12.1 26
Panc-354 29.5 32
JH-024 50.0 39
Colon CCR-020 51.6 28
CCR-025 35.6 39
CCR-029 33.5 35
CCR-030 34.3 28
Gastric Gastric-008 53.3 31
Gastric-010 2.5 38
During the treatment, complete remissions (CR) of tumors were also seen in animals bearing the following xenografts: Pulm-005 (7 CR/7 mice), Pulm-016 (10 CR/10 mice) and Gastric-010 (9 CR/9 mice).
Conclusion:
The treatment with PM060184 demonstrated significant in vivo antitumor activity in patient-derived xenografts of human NSCLC, pancreas, colon and gastric tumors.
La Presentación Demuestra cómo éste fármaco mejora el índice terapéutico en comparación con trabectedina y suprime en mayor medida la actividad de EWSFLI1, una proteína oncogénica que tiene un papel crucial en el sarcoma de Ewing, una enfermedad huérfana con pocas opciones de tratamiento.
El sarcoma de Ewing es un tumor pediátrico que se caracteriza por presentar una anomalía genética denominada traslocación (ruptura mecánica y la posterior reconexión de dos cromosomas diferentes). La traslocación tiene lugar entre los cromosomas 11 y 22 y se denomina t(11;22) o EWS/FLI1.
Actualmente, se sabe que las células de sarcoma de Ewing dependen del programa transcripcional de EWS/FL11 para su supervivencia, siendo un objetivo terapéutico suprimir la actividad de EWS/FL11. PM01183 ha demostrado este efecto, así como su sinergia con irinotecán para suprimir el crecimiento tumoral en esta enfermedad.
Además, el estudio confirma que PM01183 tiene un excelente perfil farmacológico, lo que sugiere que sus efectos pueden reproducirse en humanos. Todo ello, según los autores del estudio, pone de relieve que la traslación clínica de PM01183 como tratamiento dirigido específicamente a EWS/FL11, tanto en monoterapia como en combinación con irinotecán, está justificada.
**********************************************
BACKGROUND:
Ewing sarcoma is a pediatric malignancy characterized by the fusion of the EWSR1 and FLI1 genes, which creates a constitutively activated transcription factor, EWS/FLI1. It is widely known that Ewing sarcoma cells depend on the transcriptional program of EWS/FLI1 for cell survival. Therefore, the goal of this research is to develop and clinically translate small molecules that suppress EWS/FLI1 activity. We have previously reported that the natural product trabectedin suppresses EWS/FLI1 activity. In addition, the compound synergizes with irinotecan to suppress Ewing sarcoma tumor growth. However, the compound suffers from a narrow therapeutic index that limits the poisoning of EWS/FLI1 in patients. In this report, we show that the trabectedin analog PM01183 has improved targeting of EWS/FLI1 and preserved synergy with irinotecan. In addition, the compound is known to have a dramatically improved therapeutic index suggesting improved activity of this compound in the clinic.
METHODS:
In this report, we characterize the mechanism of suppression of EWS/FLI1 by trabectedin using confocal immunocytochemistry and chromatin immunoprecipitation. We show enhanced suppression of EWS/FLI1 by PM01183 using the Fluidigm platform and confirm the results with a luciferase reporter construct and high-content quantitative PCR. Finally, we tested the ability of PM01183 to suppress tumor growth in xenograft models of Ewing sarcoma both in the absence and presence of irinotecan.
RESULTS:
PM01183 more effectively suppressed the gene signature of EWS/FLI1 than the parent compound trabectedin. In addition, the drug re-localizes EWS/FLI1 away from target genes in the nucleus leading to suppression of these EWS/FLI1 targets. These results are consistent with the activity of the parent compound, trabectedin, that blocks binding of EWS/FLI1 to chromatin. More importantly, the drug causes a regression of a TC32 xenograft and markedly suppresses growth of a TC71 xenograft when combined with irinotecan. Finally, PM01183 has a substantially improved pharmacologic profile in patients in comparison to trabectedin suggesting that these effects are bio-achievable in patients.
CONCLUSIONS:
In comparison to trabectedin, we have shown that its structural analog, PM01183 shows enhanced suppression of an EWS/FLI1 gene signature and preserves the synergy with irinotecan that we previously reported. We suggest a mechanistic basis for this activity against EWS/FLI1 and show excellent activity against Ewing sarcoma xenografts. Together, these results suggest that the clinical translation of PM01183 as an EWS/FLI1 targeted therapy both alone and in combination with irinotecan is warranted.
Background:
PM060184 is new marine derived tubulin-binding agent originally isolated from the sponge Lithoplocamia lithistoides. PM060184 has shown potent antitumor activity in vivo against a panel of different tumor xenografted models such as colon, gastric, NSCLC, prostate and renal. Also, PM060184 has demonstrated to have a potent in vitro and in vivo activity in P-gp overexpressing cells. PM060184 is currently under evaluation in Phase I clinical studies in patients with advanced cancer diseases.
Material and Methods:
Athymic female nu/nu mice were subcutaneously implanted with H460 (NSCLC). Tumor bearing animals were randomly allocated into experimental groups (efficacy or pharmacokinetics -PK-). The animals belonging to the efficacy study received three iv doses in a weekly (q7dx3) schedule of PM060184 at 16 mg/kg or placebo. The antitumor activity was followed by the change in tumor volume for treated and placebo groups. The PK group received a single dose of PM060184 at 16 mg/kg. Then, plasma, tissue (brain, spleen, lung, muscle and heart) and tumor samples (N=3-4/sampling time) were collected at different times and up to 96 h post-administration. Tissue and tumor samples were diluted and homogenized using Precellys®24 bead beating technology. Once homogenized the samples were processed as per plasma. PM060184 was detected in plasma, tissue and tumor extracts by electrospray ionization/tandem mass spectrometry after extraction by supported liquid extraction (SLE).
Results:
The mean maximum plasma concentration (Cmax) was 2,452.5 ng/mL. The area under curve (AUC) was 2,963 ng*hr/mL. The plasma clearance was 5,398.5 mL/hr/kg. The volume of distribution at steady state was 880.7 mL/kg. The terminal half-life was 4.7 hr. The AUC0-tlast values for brain, spleen, lung, muscle and heart were 216.2, 7,402.9, 3,857.7, 2,614.6 and 2,929.5 ng*hr/g, respectively; however the AUC value for H460 xenografted tumors was 51,321.4 ng*hr/g (tlast is 96 hours for tumor, 8 hours for brain and 24 hours for the other tissues).
Conclusion:
PM060184 showed similar plasma and tissue pharmacokinetics properties as well as preferential tumor distribution until 96 h after an iv administration in mice bearing H460 xenografted tumors.
Estudio de Sonia Ávila y cols. (“Synergistic combination of Trabectedin and Olaparib in breast cancer tumor cell lines”) revela a nivel molecular el efecto sinérgico que se obtiene con el uso combinado de trabectedina y olaparib en líneas de células tumorales de cáncer de mama. Se evidencia que cuando se administran de forma combinada (olaparib a 5KM y variando las concentraciones de trabectedina de 0.05 a 2.5 nM) se desencadena un fuerte efecto apoptótico en las células cancerígenas. El efecto sinérgico de ambos fármacos parece ser el resultado de una alta acumulación roturas de doble cadena de ADN (double-strand breaks) para causar la muerte celular.
Abstrac :
Trabectedin (Yondelis, ET-743) is a marine-derived antitumor agent that is currently used for the treatment of sarcoma and, in combination with pegylated-liposomal doxorubicin, of platinum-sensitive ovarian cancer patients. After binding to the DNA minor groove, trabectedin induces a potent transcription inhibition on tumor cells and tumor-associated macrophages. The resolution of functional DNA adducts generated by the drug is known to occur through the coordinated action of multiple DNA repair pathways, including homologous recombination (HR), a process that gives rise to double-strand breaks (DSBs). Trabectedin treatment at nanomolar concentrations does indeed produce a high proportion of DSB-positive tumor cells with abundant γ-H2AX foci and an S-phase delay/arrest by activation of the DNA replication checkpoints. We had previously shown the synergism (CI < 1) of the combination of Trabectedin with Olaparib (AZD-2281) in the breast cancer cell lines HCC-1937, MCF-7, MDA-MB-231 and MDA-MB-436. In this work we have investigated the mechanism of this synergistic effect at the molecular level. While the treatment with either compound alone (0.05 nM Trabectedin or 5 μM Olaparib for 72 hours) induced only a mild antiproliferative effect, the combination of both compounds at the mentioned concentrations induced strong apoptosis in all the breast cancer cell lines. Exposure to 0.5 and 2.5 nM Trabectedin for 72 hours induced a clear accumulation of γ-H2AX foci. Exposure to Olaparib alone induced only a mild DNA damage at 72 hours with all the concentrations tested. Olaparib induced a clear inhibition of PARylation at concentrations from 1-2.5 μM of the compound. The combination of both drugs, keeping Olaparib at 5 μM and varying the concentrations of Trabectedin from 0.05 to 2.5 nM, demonstrated a synergistic effect on the accumulation of histone H2AX phosphorylation, as analyzed both by western blotting and immunofluorescence microscopy. When comparing all these results, it was clearly seen that, although Trabectedin or Olaparib generated a considerable amount of DSBs, the combination of both drugs induced a higher proportion of DNA damage that remained at very high levels even after 72 hours of treatment. Thus, the observed synergistic effect seems to be the result of higher accumulation of DSBs after the administration of the combination of Trabectedin with Olaparib.
C. S. RUGABER . AP .
C. S. RUGABER The Associated Press
Washington -- Un medicamento experimental ha mostrado resultados alentadores en el tratamiento del cáncer de mama en una prueba clínica preliminar, informó el domingo el gigante farmacéutico Pfizer.
El laboratorio, el segundo mayor del mundo, dijo que el medicamento evitó el empeoramiento del cáncer de pecho durante 20.2 meses en una prueba entre 165 pacientes. Los medicamentos que usan actualmente tienen un efecto de 10.2 meses. El medicamento, conocido como palbociclib, pertenece a una nueva clase de medicinas que actúan directamente sobre proteínas específicas para bloquear los tumores.
Los resultados no fueron tan positivos como algunos reportados anteriormente en el estudio, dijo Erik Gordon, profesor de Negocios de la Universidad de Michigan, quien estudia la industria biomédica pero no participó en el estudio.
...