Cancer cells avoid apoptosis by a variety of genetic and epigenetic mechanisms. We are investigating the induction of apoptosis by activation of death receptors for the ligand tumor necrosis factor-related apoptosis inducing ligand (TRAIL) in breast and ovarian cancer cells. Previously, we have shown that many breast and ovarian cancer cell lines are resistant to the induction of apoptosis by TRAIL, the ligand for the death receptors DR4 and DR5. We have demonstrated that resistance to TRAIL-induced apoptosis can be overcome by co-incubation of the cells with chemotherapeutic agents, semi-synthetic retinoids (such as 4HPR), or molecularly targeted agents (such as anti-HER-2 antibodies). Our current work utilizes biochemical and genetic approaches to identify mechanisms that regulate the induction of death by TRAIL ligand in breast and ovarian cancer cells. Recently, we have shown that TRAIL selectively kills triple-negative breast cancer cells that have mesenchymal features. Ongoing work is exploring this observation further using clinically relevant TRAIL agonists alone and incombination with other targeted agents. We are also investigating the molecular basis for this selectivity. Triple negative breast cancer, defined by the absence of hormone receptors and the absence of HER-2 amplification has a poor prognosis and at present can only be treated with chemotherapy. These data suggest that TRAIL agonists may have therapeutic efficacy in a subset of triple negative breast cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC007263-19
Application #
8350057
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
2011
Total Cost
$377,005
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Dine, Jennifer L; O'Sullivan, Ciara C; Voeller, Donna et al. (2016) The TRAIL receptor agonist drozitumab targets basal B triple-negative breast cancer cells that express vimentin and Axl. Breast Cancer Res Treat 155:235-51
Endo Greer, Yoshimi; Lipkowitz, Stanley (2016) ONC201: Stressing tumors to death. Sci Signal 9:fs1
Greer, Yoshimi Endo; Lipkowitz, Stanley (2015) TIC10/ONC201: a bend in the road to clinical development. Oncoscience 2:75-6
Garimella, Sireesha V; Rocca, Andrea; Lipkowitz, Stanley (2012) WEE1 inhibition sensitizes basal breast cancer cells to TRAIL-induced apoptosis. Mol Cancer Res 10:75-85
Murrow, Lyndsay M; Garimella, Sireesha V; Jones, Tamara L et al. (2010) Identification of WEE1 as a potential molecular target in cancer cells by RNAi screening of the human tyrosine kinome. Breast Cancer Res Treat 122:347-57
Chavez, Kathryn J; Garimella, Sireesha V; Lipkowitz, Stanley (2010) Triple negative breast cancer cell lines: one tool in the search for better treatment of triple negative breast cancer. Breast Dis 32:35-48
Rahman, Monzur; Pumphrey, Janet G; Lipkowitz, Stanley (2009) The TRAIL to targeted therapy of breast cancer. Adv Cancer Res 103:43-73
Rahman, Monzur; Davis, Sean R; Pumphrey, Janet G et al. (2009) TRAIL induces apoptosis in triple-negative breast cancer cells with a mesenchymal phenotype. Breast Cancer Res Treat 113:217-30
Kato, Sumie; Sadarangani, Anil; Lange, Soledad et al. (2008) 2-methoxyestradiol mediates apoptosis through caspase-dependent and independent mechanisms in ovarian cancer cells but not in normal counterparts. Reprod Sci 15:878-94