birinapant and Neoplasms--Cystic--Mucinous--and-Serous
birinapant has been researched along with Neoplasms--Cystic--Mucinous--and-Serous* in 2 studies
Trials
1 trial(s) available for birinapant and Neoplasms--Cystic--Mucinous--and-Serous
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Pharmacodynamic markers and clinical results from the phase 2 study of the SMAC mimetic birinapant in women with relapsed platinum-resistant or -refractory epithelial ovarian cancer.
Inhibitors of apoptosis proteins (IAPs) are key regulators of apoptosis and are frequently dysregulated in ovarian cancer. It was hypothesized that blocking IAPs with birinapant would increase tumor cell death and result in objective responses for women with platinum-refractory and -resistant ovarian cancer.. In this phase 2, Cancer Therapy Evaluation Program-sponsored study, patients received birinapant at 47 mg/m(2) on days 1, 8, and 15 of 28-day cycles. Pharmacokinetics were obtained during cycle 1. Plasma, peripheral blood mononuclear cells (PBMCs), and percutaneous tumor biopsy samples were collected before cycle 1 and after 6 weeks. The primary endpoint was an objective response or progression-free survival lasting greater than 6 months in a mini-max design.. Eleven patients received birinapant; after this, accrual was terminated for lack of a clinical benefit. Birinapant was well tolerated, with predominantly grade 2 adverse events and 1 case of grade 3 lymphopenia. Pretreatment biopsy samples and PBMCs were collected; paired posttreatment biopsy samples and PBMCs were collected from 7 and 10 patients, respectively. There was consistent downregulation of cellular inhibitor of apoptosis protein 1 in tumors (P = .016) and PBMCs (P < .01). Procaspase 3 also decreased in tumors (P = .031) and PBMCs (P < .01); cleaved caspase 3 colocalized with H2A histone family member X (γ-H2AX) in tumors after birinapant exposure. Peripheral T and B cells decreased significantly after treatment, but natural killer cells did not (P = .04, P = .05, and P = .43, respectively).. Birinapant shows consistent target suppression in vivo without single-agent antitumor activity in this small population. Single-agent pharmacodynamics are necessary to understand the drug's mechanism of action and set the stage for rational combination therapy. Preclinical studies are ongoing to identify optimal synergistic combinations for future clinical trials. Topics: Adenocarcinoma, Clear Cell; Aged; Antineoplastic Agents; Apoptosis Regulatory Proteins; B-Lymphocytes; Carcinoma, Endometrioid; Carcinoma, Ovarian Epithelial; Caspase 3; Dipeptides; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Indoles; Inhibitor of Apoptosis Proteins; Intracellular Signaling Peptides and Proteins; Killer Cells, Natural; Leukocytes, Mononuclear; Lymphocyte Count; Lymphopenia; Middle Aged; Mitochondrial Proteins; Neoplasms, Cystic, Mucinous, and Serous; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Platinum Compounds; T-Lymphocytes; Treatment Failure; Treatment Outcome; Ubiquitin-Protein Ligases | 2016 |
Other Studies
1 other study(ies) available for birinapant and Neoplasms--Cystic--Mucinous--and-Serous
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An apoptosis-enhancing drug overcomes platinum resistance in a tumour-initiating subpopulation of ovarian cancer.
High-grade serous ovarian cancers (HGSCs) are deadly malignancies that relapse despite carboplatin chemotherapy. Here we show that 16 independent primary HGSC samples contain a CA125-negative population enriched for carboplatin-resistant cancer initiating cells. Transcriptome analysis reveals upregulation of homologous recombination DNA repair and anti-apoptotic signals in this population. While treatment with carboplatin enriches for CA125-negative cells, co-treatment with carboplatin and birinapant eliminates these cells in HGSCs expressing high levels of the inhibitor of apoptosis protein cIAP in the CA125-negative population. Birinapant sensitizes CA125-negative cells to carboplatin by mediating degradation of cIAP causing cleavage of caspase 8 and restoration of apoptosis. This co-therapy significantly improves disease-free survival in vivo compared with either therapy alone in tumour-bearing mice. These findings suggest that therapeutic strategies that target CA125-negative cells may be useful in the treatment of HGSC. Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; CA-125 Antigen; Carboplatin; Caspase 8; Dipeptides; Drug Resistance, Neoplasm; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Indoles; Inhibitor of Apoptosis Proteins; Membrane Proteins; Mice; Neoplasm Transplantation; Neoplasms, Cystic, Mucinous, and Serous; Ovarian Neoplasms; Recombinational DNA Repair; Up-Regulation | 2015 |