This technology uses a modified form of ATF5 to inhibit the proteins CEBPB, CEBPD and CCDC6, which have been shown to enhance cancer cell survival, proliferation, and migration.
Unmet Need: Effective inhibitors of CEPBB, CEBPD, and CCDC6 to treat cancer
Despite major advances in cancer research, many tumor types still have an unfavorable prognosis and are difficult to treat with traditional chemotherapeutics. Thus, in recent years, drug development has largely focused on inhibiting specific genes that have been identified as being important to cancer cell growth. The genes CEBPB, CEBPD and CCDC6 have previously been shown to play active roles in the regulation of cancer cell proliferation, survival and migration, and interference with the expression of these genes has proved to have a detrimental effect on cancer cells. However, there is of yet no therapeutic approach to target these genes for cancer treatment.
The Technology: Cell-penetrating dominant-negative ATF5 to inhibit cancer cell survival proteins
This technology uses the basic leucine zipper transcription factor (ATF5) as a target for cancer treatment. Specifically, the use of a cell-penetrating dominant-negative form of ATF5 is used to target CCAAT/enhancer-binding protein beta and delta (CEBPD and CEBPB), and coiled-coil domain containing 6 (CCDC6), which act to enhance cancer cell survival. By binding to complementary proteins to form an inactive heterodimer, these truncated proteins act as specific inhibitors for such partners, inducing cancer cell death. This technology also suggests that the dominant-negative forms of the enhancer proteins CEBPD, CEBPB and CCDC6 themselves may also represent potential anti-cancer drugs.
This technology has been validated in human PC3 prostate tumor cells.
Applications:
- Targeted anti-cancer treatment
- Identification of alternate dominant-negative inhibitors
- Research tool for the study of cancer cell protein expression and regulation
Advantages:
- Regulates the long-term growth and survival of tumor cells
- Less invasive form of treatment
- Safe and effective against treatment-resistant cancers
Lead Inventor:
Lloyd Greene, Ph.D.
Patent Information:
Patent Pending
Related Publications:
Karpel-Massler G, Horst BA, Shu C, Chau L, Tsujiuchi T, Bruce JN, Canoll P, Greene LA, Angelastro JM, Siegelin MD. “A synthetic cell-penetrating dominant-negative ATF5 peptide exerts anticancer activity against a broad spectrum of treatment-resistant cancers” Clin Cancer Res. 2016 Sep 15; 22(18): 4698-4711.
Cates CC, Arias AD, Nakayama Wong LS, Lamé MW, Sidorov M, Cayanan G, Rowland DJ, Fung J, Karpel-Massler G, Siegelin MD, Greene LA, Angelastro JM. “Regression/eradication of gliomas in mice by a systemically-deliverable ATF5 dominant-negative peptide” Oncotarget. 2016 Mar 15; 7(11): 12718-12730.
Arias A, Lamé MW, Santarelli L, Hen R, Greene LA, Angelastro JM. “Regulated ATF5 loss-of-function in adult mice blocks formation and causes regression/eradication of gliomas” Oncogene. 2012 Feb 9; 31(6): 739-751.
Li G, Li W, Angelastro JM, Greene LA, Liu DX. “Identification of a novel DNA binding site and a transcriptional target for activating transcription factor 5 in c6 glioma and mcf-7 breast cancer cells” Mol Cancer Res. 2009 Jun; 7(6): 933-943.
Mason JL, Angelastro JM, Ignatova TN, Kukekov VG, Lin G, Greene LA, Goldman JE. “ATF5 regulates the proliferation and differentiation of oligodendrocytes” Mol Cell Neurosci. 2005 Jul; 29(3): 372-380.
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