ADC MI130004 , Otro avance que será presentado por la Compañía es el desarrollo del anticuerpo conjugado, MI130004, que combina el anticuerpo monoclonal trastuzumab (que se une a la proteína de superficie HER-2) y el compuesto de origen marino PM050489 .
Los resultados de este estudio demuestran que el tratamiento con MI130004 produce un marcado y duradero efecto antitumoral en modelos preclínicos de tumores de mama que sobreexpresan HER2. Los datos destacan el incremento de la supervivencia de los animales tratados y demuestran el potencial de este nuevo producto.
*****************************************************************
Abstract Number: 2480
Presentation Title: MI130004, a new antibody-drug conjugate, induces strong, long-lasting antitumor effect in HER2 expressing breast tumor models .
Presentation Time:
Monday, Apr 20, 2015, 1:00 PM - 5:00 PM .
Author Block :
Pablo M. Aviles1, Maria Jose J. Guillen1, Alberto Gallardo2, Maria Virtudes Cespedes3, Ramon Mangues2, Heiner Fiebig4, Natalie Hartman4, Juan Manuel Dominguez1, Luis Francisco Garcia1, Carlos Galmarini1, Carmen Cuevas1. 1PharmaMar S.A., Madrid, Spain; 2Institut d`Investigacions Biomèdiques Sant Pau and CIBER-BBN, Barcelona, Spain; 3Institut d`Investigacions Biomèdiques Sant Pau and CIBER-BBN, Spain., Barcelona, Spain; 4Oncotest GmbH, Freiburg, Germany .
Abstract Body: Background:
Antibody-drug conjugates (ADC`s) have emerged as powerful tools for the treatment of cancer, combining the potency of cytotoxic molecules with the selectivity of antibodies targeted towards specific antigens. Marine compounds represent an interesting opportunity worth exploring as they possess the requirements needed to be considered promising payloads. The in vivo results obtained with a new ADC, MI130004, in HER2 expressing breast tumors are presented here.
Materials and Methods:
To evaluate the long lasting antitumor effect induced by MI130004, immunodefficient female mice were subcutaneously implanted with HER2 expressing breast lines namely, JIMT-1, BT-474 and MAXF574.Tumor (ca. 100 mm3) bearing
animals were randomly allocated (Day 0) to receive MI130004 (10mg/kg), trastuzumab (30 or 10 mg/kg) or placebo (N=8-10/group). Intravenous treatments were weekly administered for 5 consecutive weeks and then, tumor volume growth was recorded 2-3 times per week. For survival evaluation, time to endpoint was define as the time from Day 0 to death as a results of tumor growth (>2000 mm3) or any other cause (e.g., tumor necrosis). Statistical differences were assessed by Kaplan-Meier curves with the log rank test. The follow-up period was extended until 90 (MAXF574) or 120 days (JIMT-1 and BT-474) after the initiation day (Day 0). Then, surviving animals were sacrificed, tumor (or skin around the former tumor site) dissected free, formalin fixed and paraffin embedded for histopathology evaluations.
Results:
The treatment with MI130004 induced a long lasting antitumor effect with statistically significant increases in median survival time compared to either placebo ( P = 0.0336, P = 0.0001 and P < 0.0001 for BT-474, JIMT-1 and MAXF574, respectively ) or trastuzumab treatments ( P = 0.0005 and P < 0.0001 for JIMT-1 and MAXF574, respectively ). Seventy one percent of mice xenografted with JIMT-1 and treated with MI130004 survived up to Day 120. Out of them, 40% experienced a complete tumor remission ( tumor < 63 mm3 ). All animals originally xenografted with BT-474 experienced complete tumor remissions by Day 120. On Day 90, 90.0% of the population xenografted with MAXF574 survived and 55.6% of these experienced complete tumor remission.
Conclusions:
The treatment with MI130004 on mice bearing HER2 expressing breast tumors resulted in strong, long lasting antitumor activity, including complete tumor remissions. These results strongly suggest that MI130004 is a new ADC with extraordinary therapeutic anti-cancer properties. b>
P.J.: PM1183 inhibe de manera selectiva la transcripción activada y también bloquea la vía de reparación de ADN llamada nucelotide excision repair (NER) provocando una acumulación letal de daños en el material genético, que induce la muerte por apoptosis de las células tumorales.
PM01183 iniciara este año 2015 Dos Ensayos Pivotales en la indicaciones de Cáncer de Ovario Resistente a Platinos y en SCLC ( Pulmón Small ) .
*********************************************************************************
Sera Presentado este Lunes en el Congreso Anual de la Asociación Americana para la Investigación del Cáncer (AACR) que Tiene lugar en Filadelfia (EE.UU.) del 18 al 22 de abril.
Abstract Number: 2520
Presentation Title: Synergistic combination of lurbinectedin and PARP inhibitors in breast cancer tumor cell lines .
Abstrac que se Presentara el proximo Lunes dia 20 en el Congreso de la AACR .
Presentation Time: Monday, Apr 20, 2015, 1:00 PM - 5:00 PM
Author Block:
Gema Santamaría, Sonia Avila, Victoria Moneo, Carmen Cuevas, Luis F. García-Fernández, Carlos M. Galmarini. PharmaMar S.A., Madrid, Spain
Abstract Body:
Lurbinectedin (PM1183) is a new tetrahydroisoquinoline derivative currently evaluated in phase II trials in BRCA1-mutated breast cancer and NSCLC patients. Two pivotal trials (in platinum-resistant ovarian cancer and in SCLC) will be launched in 2015.
PM1183 shows antitumor activity against a wide variety of tumor cells with mean IC50 values in the low nanomolar range. In living cells, PM1183 inhibits trans-activated transcription and blocks NER-dependent DNA repair inducing the formation of dsDNA breaks and the collapse of replication forks that need to be repaired by homologous recombination (HR). As expected, PM1183 is more active against homologous recombination (HR)-deficient cell lines. In this work, we evaluated the in vitro antitumor effect of PM1183 when combined with the PARP inhibitors ABT-88 (Veliparib, PARP-1 and -2), AZD-2281 (Olaparib, PARP-1), BSI-201 (Iniparib, PARP-1) and BMN-673 (PARP-1 and -2) (Selleck Chemicals, Houston, TX, USA) in a panel of human breast carcinoma cells with different BRCA1 status, including MCF-7 (BRCA1 +/+), MDA-MB-231 (BRCA1 +/-), HCC-1937 (BRCA1 -/-) and MDA-MB-436 (BRCA1 -/-).
The combination index (CI) of each different drug-drug combination was calculated by applying the Chou and Talalay method. Different degrees of synergism (CI < 1) were recorded when PM1183 was combined with AZD-2281 (Olaparib) and BMN-673, depending on the tumor cell line and the conditions tested. The highest degree of synergism with Olaparib was observed in MDA-MB-436 cells followed by MDA-MB-231, MCF7 and HCC-1937 cells. The highest degree of synergism with BMN-673 was observed in MCF-7 cells followed by MDA-MB-231 and HCC-1937 cells. In MDA-MB-231 cells, both combinations led to a synergistic induction of γ-H2AX expression and PARP-1 cleavage, as analyzed by western blot. Collectively, our results indicate that the combination of PM1183 and PARP inhibitors (Olaparib and BMN673) induces an artificial synthetic lethality that can be advantageously used to kill several breast cancer cells, independently from their BRCA1 status.
Sera Presentado este Lunes en el Congreso Anual de la Asociación Americana para la Investigación del Cáncer (AACR) que tiene lugar en Filadelfia (EE.UU.) del 18 al 22 de abril.
Presentation Title:
Lurbinectedin (PM01183) synergizes in vivo the antitumor activity of doxorubicin in SCLC tumor xenografts .
* Estos resultados han proporcionado las bases para el inicio de un ensayo clínico de la combinación en pacientes con cáncer microcítico de pulmón.
Abstract Number: 2542 .
Presentation Time: Monday, Apr 20, 2015, 1:00 PM - 5:00 PM .
Author Block: Maria Jose Guillen, Oscar Cataluña, Mandy Palomares, Raquel Lopez, Praxedes Nuñez, Carmen Cuevas, Pablo M. Aviles. PharmaMar S.A., Madrid, Spain
Abstract Body:
Background:
Lurbinectedin (PM01183) is a synthetic tetrahydroisoquinoline alkaloid currently evaluated as single agent and in combination in phase I and II clinical trials for solid tumors and hematological malignancies. In living cells, PM01183-DNA adducts stall replication and transcription giving rise to double strand breaks, inducing accumulation of cells in the S-phase of the cell cycle and triggering apoptosis. Studies aimed at defining the in vivo synergism of PM01183 and doxorubicin in the treatment of Small Cell Lung Cancer (SCLC) xenografted tumors are presented here.
Material and Methods:
Athymic nude mice were implanted with SCLC cells (NCI-H82 or NCI-H526). Mice bearing tumors (ca. 150 mm3) were allocated (N=6-8/group) to experimental groups, namely: placebo;
PM01183 at MTD (0.18 mg/kg), 0.75MTD, 0.5MTD and 0.25MTD; doxorubicin at their MTD (8.0 mg/kg), 0.75MTD, 0.5MTD and 0.25MTD; and, PM01183 combined with doxorubicin at (1+1), (0.75+0.75), (0.50+0.50) and (0.25+0.25) MTDs. All treatments were given intravenously once per week during the placebo-treated survival time. The antitumor effect induced by the treatments was analyzed using two-tailed Mann-Whitney U test. Also, the synergism was defined by the combination index (CI) determined by the CI-isobol method.
Results:
In both experiments, the combination of PM01183 and doxorubicin resulted in stronger antitumor effect (P < 0.05) than that obtained with the more active single agent at the highest dose (MTD level). Analyses of the results by the CI-isobol method indicated that, after the treatment with PM01183 plus doxorubicin in the SCLC models resulted in an additive (at Fa= 0.97, CI= 1.05 ) or synergistic (at Fa= 0.97, CI= 0.66 ) effect.
Conclusion:
An improved (additive or synergism) in vivo antitumor activity was recorded after the treatment with PM01183 plus doxorubicin of mice bearing SCLC xenografted tumors.
Publicado por Marcial Parraguez .
La sepsis es una infección en el organismo derivada de una enfermedad en un punto local del cuerpo, lo que puede provocar incluso la muerte, en algunos casos.
Hoy en día se considera la sepsis como una pandemia, ya que su mortalidad y el alto costo para quienes la padecen la hacen muy difícil de tratar.
Según describe la Biblioteca de Medicina de EEUU, se trata de una condición “en la cual el cuerpo tiene una respuesta grave a bacterias u otros microorganismos. Esta respuesta se puede denominar síndrome de respuesta inflamatoria sistémica (SRIS)”.
Por parte de la Organización Mundial de la Salud son entre 20 a 30 millones de personas las que año a año sufren algún cuadro de sepsis, transformándola en la principal causa de muerte por infección en todo el planeta.
La sepsis llega incluso a superar al infarto al miocardio y también al cáncer, según estadísticas de la OMS un tercio de los pacientes internados en Cuidados Intensivos muere a causa de este síndrome.
Bajo este síndrome se presentan caídas en la presión arterial, pudiendo incluso ocasionar un shock. Los órganos principales como los riñones, hígado, pulmones y hasta el sistema nervioso central deja de funcionar debido a una circulación sanguínea insuficiente.
Tratamiento :
Según los Institutos Nacionales de la Salud de Estados Unidos, los síntomas de la sepsis son causados por productos químicos que libera el cuerpo, y puede ser sólo una infección bacteriana la que activa en cualquier lugar del cuerpo una respuesta en defensa que puede causar sepsis.
Por lo general, las personas con sepsis están hospitalizadas en la Unidad de Cuidados Intensivos (UCI), y los antibióticos se administran por a través de las venas.
Esta infección, por lo general, se diagnostica luego de un examen de sangre, sin embargo, es posible que éstos no arrojen conclusiones determinantes ya que si la persona ha estado consumiendo antibióticos es probable que en los resultados no salga a la luz ninguna infección.
A menudo esta enfermedad es mortal, sobre todo en personas cuyo sistema se encuentra debilitado o para quienes estén bajo una enfermedad prolongada.
Por su parte, Araya dice que “a través de un mecanismo multidisciplinario es posible tratarla, y el tratamiento es en base a protocolos antibióticos y de soporte de órganos, hemodinámico, renal, etc.”, y agrega que éste “consiste en protocolos que permiten orientar a un manejo de soporte y de erradicación de foco y la erradicación de foco es en base a antibióticos y a drenaje quirúrgico, si es necesario”.
Con respecto al costo de la enfermedad el especialista aclara que “habitualmente los pacientes con sepsis están en unidades de cuidados intensivos (UCI) que son de altos costo y los tratamientos de soporte son de alta tecnología, lo mismo pasa con los antibióticos ya que son de amplio espectro”.
Como el daño de la sepsis pasa por una “disminución en el flujo sanguíneo” puede que los órganos vitales queden con secuelas a largo plazo.
Respecto a la esperanza de vida, el doctor aclara que es difícil determinar una cantidad exacta de tiempo. “Depende de adonde llegue el paciente y de la infraestructura que tenga el recinto asistencial y de la logística que tenga el hospital. Si se hace rápido y bien, hay una buena sobrevida, una mayor al 90% pero si el hospital no tiene una buena infraestructura y logística la sobrevida baja del 70%”.
By Anette Breindl, Senior Science Editor .
PHILADELPHIA – Patients treated with Merck & Co Inc.’s Keytruda (pembrolizumab) had better outcomes than could be achieved with their respective standards of care in melanoma and lung cancer trials. Results were presented today at the annual meeting of the American Association for Cancer Research (AACR).
Full data from the Keynote-006 study, a head-to-head comparison of Keytruda (Pembrolizumab, Merck & Co Inc.) and Yervoy (ipilimumab, Bristol-Myers Squibb Co.) for the treatment of metastatic melanoma, showed that Keytruda was “superior on all counts” to Yervoy, Keynote-006 study lead Antoni Ribas said.
Patients receiving Keytruda had better overall survival, better progression-free survival, a higher overall response rate and lower rates of adverse reactions.
The findings “should change the paradigm of treatment … the standard of care should quickly shift to giving a PD-1 antibody,” Ribas said. He noted that although the Keynote-006 trial tested Keytruda, he believes similar effects would be achieved with Opdivo (nivolumab, Bristol-Myers Squibb Co.), which also targets PD-1.
This should also lead to label changes for the drug, which is so far approved for use only after both Yervoy and Zelboraf have failed.
“I assume with this data the FDA will soon change the label,” Ribas said, although he added that Medicare already allows up-front use of Keytruda, and so “the field is going a little bit faster than the FDA.”
The somewhat surprising label reflects partly how young the immunotherapy space still is in terms of its regulatory history. (See BioWorld Today, Sept. 7, 2014.)
When Keytruda was approved, Merck’s senior vice president of global clinical development Roy Baynes told BioWorld Today, “the unmet need was in patients who had failed Yervoy.”
But the new data show, Baynes said, that Keytruda is “superior” to Yervoy, and the company is seeking its approval for metastatic melanoma patients who have not previously been treated with Yervoy.
In the Keynote-006 trial, 834 patients with metastatic melanoma were randomly assigned to one of the treatment arms. They either received Yervoy, or Keytruda dosed every two or three weeks. The Keynote-006 trial was halted early in March after an interim analysis indication that the trial had met its primary and secondary endpoints of overall and progression-free survival, respectively.
At AACR, Ribas, presented the details of the trial, which were concurrently published in the April 19, 2015, online issue of The New England Journal of Medicine.
Overall survival at one year for patients who received pembrolizumab was 74 percent and 68 percent in the two Keytruda groups, significantly higher than the 58 percent for patients treated with Yervoy. After six months, the response rate was 45 percent for patients taking Keytruda compared to 26 percent for those who received Yervoy. Overall response rates were at about 33 percent for both Keytruda groups, as opposed to 12 percent for Yervoy.
Keytruda also improved overall survival in lung cancer patients treated with the drug. Edward Garon showed data from the Keynote-001 non-small cell lung cancer expansion cohort, nearly 500 patients were treated with Keytruda.
Not surprisingly, the patients with the highest levels of PD-L1 staining benefited most from the treatment.
Compared to chemotherapy, such patients had a higher response rate, and the median overall survival ‑ which was less than nine months for patients with intermediate or low levels of PD-L1 ‑ has not yet been reached for patients with high levels of PD-L1 expression on their tumors.
In patients with high levels of PD-L1, 45 percent responded to the drug. Merck announced on Sunday that it has filed a supplementary biologics license application for Keytruda in advanced non-small cell lung cancer based on the trial results.
Garon said that benefit “substantially exceeds that expected from chemo” in patients with high staining tumors, but is still “compelling” for patients with intermediate levels of staining.
...
EFE. 19.04.2015 -
Científicos del Instituto de Investigación Sanitaria de Valencia (INCLIVA) han identificado una serie de moléculas que crean resistencias a los tratamientos para los casos de cáncer de mama triple negativo, el más agresivo, lo que daría pie a diseñar nuevas terapias con mejor respuesta para las pacientes.
Fuentes de este instituto con sede en Valencia han informado de que el estudio, coordinado por Pilar Eroles, directora del laboratorio de Oncología Molecular y Celular del Grupo de Investigación de biología del cáncer de mama del INCLIVA, ha sido publicado en la revista internacional Journal of celular biochemistriy.
Sus investigaciones se centran en el estudio de los mecanismos implicados en el desarrollo y el mantenimiento del cáncer, y en particular en los mecanismos de resistencia a los tratamientos actuales, especialmente en los subtipos moleculares de cáncer de mama más agresivos, como el triple negativo.
Según Eroles, el cáncer no es una enfermedad única e incluso dentro del cáncer de mama hay diferentes subtipos según su biología molecular y los diferentes mecanismos reguladores de los procesos celulares.
En el proyecto han comparado la respuesta de una terapia microRNAs de dos subtipos moleculares de cáncer de mama, el luminal y el triple negativo, que según la investigadora "se comportan de forma muy distinta ante los diferentes tratamientos existentes".
"Buscando el porqué, hemos analizado la respuesta de los microRNAs a uno de los fármacos habituales para tratar el cáncer de mama, la doxorubicina, una terapia de quimioterapia que daña las células tumorales", explica la científica.
...
