Abstract

c-FLIP is a key anti-apoptotic factor that is over-expressed in many tumors and blocks the apoptotic machinery by interfering with FADD, caspase-8 and DR5. Significant evidence demonstrates that c-FLIP over-expression in tumors is a major cause of resistance to TRAIL-induced apoptosis. Therefore, strategies to inhibit c-FLIP action and to overcome c-FLIP-induced resistance in tumor cells may lead to novel and more effective therapies. We have discovered a bioactive peptide, ApoFLIP that antagonizes with c-FLIP and reinstates the apoptotic machinery in c-FLIP expressing cells. The major goal of this proposal is to develop and characterize drug-like variants of this peptide. These agents could provide significant enhancements in the current therapeutic strategies in hematological malignancies and other tumors that show resistance to apoptosis-inducing therapeutics.

Public Health Relevance

Research Narrative: Resistance to cancer therapeutics is one of the major hurdles in oncology. The chief cause of this resistance is evasion of apoptosis due to altered apoptotic signaling. This proposal focuses on characterization of a novel bioactive paptide that we have discovered that could remove a major apoptotic block in cancer cells and sensitize them to apoptosis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080192-07
Application #
7930578
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Thomas, John
Project Start
2009-09-15
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2012-08-31
Support Year
7
Fiscal Year
2010
Total Cost
$632,013
Indirect Cost

  Institution

Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

Bhasin, Manoj K; Ndebele, Kenneth; Bucur, Octavian et al. (2016) Meta-analysis of transcriptome data identifies a novel 5-gene pancreatic adenocarcinoma classifier. Oncotarget 7:23263-81
Bucur, Octavian; Gaidos, Gabriel; Yatawara, Achani et al. (2015) A novel caspase 8 selective small molecule potentiates TRAIL-induced cell death. Sci Rep 5:9893
Bucur, Octavian; Stancu, Andreea Lucia; Muraru, Maria Sinziana et al. (2014) PLK1 is a binding partner and a negative regulator of FOXO3 tumor suppressor. Discoveries (Craiova) 2:
Pennarun, B; Gaidos, G; Bucur, O et al. (2013) killerFLIP: a novel lytic peptide specifically inducing cancer cell death. Cell Death Dis 4:e894
Bucur, Octavian; Stancu, Andreea Lucia; Goganau, Ioana et al. (2013) Combination of bortezomib and mitotic inhibitors down-modulate Bcr-Abl and efficiently eliminates tyrosine-kinase inhibitor sensitive and resistant Bcr-Abl-positive leukemic cells. PLoS One 8:e77390
Bucur, Octavian; Pennarun, Bodvael; Stancu, Andreea Lucia et al. (2013) Poor antibody validation is a challenge in biomedical research: a case study for detection of c-FLIP. Apoptosis 18:1154-62
Bucur, O; Stancu, A L; Khosravi-Far, R et al. (2012) Analysis of apoptosis methods recently used in Cancer Research and Cell Death & Disease publications. Cell Death Dis 3:e263
Singh, Amrik; Plati, Jessica; Khosravi-Far, Roya (2011) Harnessing the tumor suppressor function of FOXO as an alternative therapeutic approach in cancer. Curr Drug Targets 12:1311-21
Plati, Jessica; Bucur, Octavian; Khosravi-Far, Roya (2011) Apoptotic cell signaling in cancer progression and therapy. Integr Biol (Camb) 3:279-96
Degli Esposti, Mauro; Tour, Julien; Ouasti, Sihem et al. (2009) Fas death receptor enhances endocytic membrane traffic converging into the Golgi region. Mol Biol Cell 20:600-15

Showing the most recent 10 out of 22 publications