Ordóñez JL,, Amaral AT,, Carcaboso AM, Herrero-Martín D, Del Carmen García-Macías M, Sevillano V, Alonso D, Pascual-Pasto G, San-Segundo L, Vila-Ubach M, Rodrigues T, Fraile S, Teodosio C, Mayo-Iscar A, Aracil M, Galmarini CM, Tirado OM, Mora J, de Álava E,.
Oncotarget 2015 .
Abstract
Recent preclinical evidence has suggested that Ewing Sarcoma (ES) bearing EWSR1-ETS fusions could be particularly sensitive to PARP inhibitors (PARPinh) in combination with DNA damage repair (DDR) agents.
Trabectedin is an antitumoral agent that modulates EWSR1-FLI1 transcriptional functions, causing DNA damage. Interestingly, PARP1 is also a transcriptional regulator of EWSR1-FLI1, and PARPinh disrupts the DDR machinery. Thus, given the impact and apparent specificity of both agents with regard to the DNA damage/DDR system and EWSR1-FLI1 activity in ES, we decided to explore the activity of combining PARPinh and Trabectedin in in vitro and in vivo experiments.
The combination of Olaparib and Trabectedin was found to be highly synergistic, inhibiting cell proliferation, inducing apoptosis, and the accumulation of G2/M. The drug combination also enhanced γH2AX intranuclear accumulation as a result of DNA damage induction, DNA fragmentation and global DDR deregulation, while EWSR1-FLI1 target expression remained unaffected.
The effect of the drug combination was corroborated in a mouse xenograft model of ES and, more importantly, in two ES patient-derived xenograft (PDX) models in which the tumors showed complete regression.
In conclusion, the combination of the two agents leads to a biologically significant deregulation of the DDR machinery that elicits relevant antitumor activity in preclinical models and might represent a promising therapeutic tool that should be further explored for translation to the clinical setting.
Estos Resultados Obtenidos en Fase Ib vienen a Confirmar que "" PM01183 Iniciara Directamente la Fase III de Registro en Pacientes con Cáncer de Pulmón de Celulas Pequeñas ( SCLC ) "" un Estudio Pivotal de Fase III que Comparará la Combinación en segunda línea contra Topotecán, el único Medicamento Aprobado en EE. UU. y Europa para esta Indicación que existe an la actualidad .
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Journal Oncology News | June 10, 2015 | ASCO 2015, Lung Cancer . By Cancer Network Staff .
Transcriptional Inhibitor With Doxorubicin Shows Promise in SCLC .
Results from a phase I study showed that transcriptional inhibitor PM01183 along with doxorubicin induced responses as a second-line treatment for patients with small-cell lung cancer (SCLC). The study (abstract 7509) was presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting held May 29 to June 2 in Chicago.
PM01183 (Lurbinectedin) inhibits transactivated transcription by targeting RNA polymerase II. It also impairs the DNA repair system known as nucleotide excision repair (NER). In vitro research has shown that it acts synergistically with doxorubicin. In this phase I trial, 21 patients who failed one chemotherapy-containing prior line of therapy received a combination of PM01183 and doxorubicin. The median age of the patients in the trial was 62 years, and 76% of patients were male; 29% had brain metastases, and 62% had bulky disease.
The confirmed response rate in the trial was 67%, including approximately 10% complete responses. The median chemotherapy-free interval (CTFI) upon entering the trial was 3.1 months, and 48% of patients were considered resistant to prior therapy. The study found that CTFI was predictive of response (P = .001), with all sensitive patients responding to the treatment and 30% of resistant patients responding. The median progression-free survival was 4.6 months.
Grade 4 neutropenia was common, occurring in 86% of patients; grade 4 thrombocytopenia occurred in 19%, and grade 4 anemia occurred in 5%. Grade 3/4 febrile neutropenia was seen in 29% of patients, while other toxicities including fatigue, anorexia, and nausea/vomiting were generally mild. Three patients did discontinue the study drug because of toxicity, and five patients (24%) are still ongoing. There were no drug-related deaths.
“The rate, depth, and length of responses that we have observed with this treatment in the second-line setting are remarkable, even in those patients that are usually considered harder to treat,” said Martin Forster, MD, PhD, of University College Hospital in London, who led the study, in a press release. “Small-cell lung cancer is an unmet clinical need with very few recent advances and the scientific community is committed to help develop new effective therapies.”
PM01183 is being evaluated in a number of malignancies, including metastatic breast cancer, various types of leukemia, and non–small-cell lung cancer.
