The Notch family is a group of evolutionarily conserved proteins (Notch1 - Notch4) that play a role in cell differentiation, patterning, proliferation, and survival. Notch signaling has been implicated in a variety of cancers, including difficult-to-treat ovarian cancer, because of its role in tumor angiogenesis (new blood vessel formation). This technology is a class of Notch protein mimics that act as inhibitors of tumor angiogenesis, as well as methods for using them in the treatment of cancers. They offer an alternative to other currently available angiogenesis inhibitors, such as vascular endothelial growth factor (VEGF) inhibitors, as a treatment for preventing tumor growth and metastasis.
Notch fusion proteins inhibit tumor growth and angiogenesis
The Notch fusion proteins provided by this technology are comprised of the extracellular domain of one of the Notch proteins, a peptide, and the Fc portion of a human antibody. They act as competitive inhibitors to block Notch signaling during angiogenesis. Notch signaling occurs downstream of VEGF signaling during angiogenesis, so this technology may offer an alternative treatment for tumors that become resistant to VEGF inhibitors. Notch signaling is also implicated in a range of disease pathologies, and it plays a role in the regulation of blood sugar and insulin levels. This makes these fusion proteins attractive therapeutic candidates for other diseases including metabolic disorders.
The Notch1 fusion proteins described by this technology have been shown to inhibit the growth of human ovarian cancer xenografts and NGP (a human neuroblastoma cell line) xenografts in a murine tumor model.
Lead Inventor:
Jan Kitajewski, Ph.D.
Applications:
- Treatment for ovarian cancer
- Treatment for metabolic disorder
- Treatment of cancers characterized by up-regulation of Notch signaling
- Treatment of cancers by restricting blood supply to tumors
- Research tool for studying Notch signaling
Advantages:
- Targets multiple cancer advancement pathways including cell growth, differentiation, and tumor angiogenesis
- Notch signaling is implicated in diverse pathologies
- Alternative therapy for tumors resistant to VEGF inhibitors
Patent Information:
Patent Pending (US 20110008342)
Patent Pending (WO/2009/025867)
Tech Ventures Reference: IR 2162
Related Publications:
Hernandez SL, Banerjee D, Garcia A, Kangsamaksin T, Cheng WY, Anastassiou D, Funahashi Y, Kadenhe-Chiweshe A, Shawber CJ, Kitajewski JK, Kandel JJ, Yamashiro DJ. "Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis." Vasc Cell. 2013 Sep 25;5(1):17.
Pajvani UB, Qiang L, Kangsamaksin T, Kitajewski J, Ginsberg HN, Accili D. "Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability." Nat Med. 2013 Aug;19(8):1054-60.
Galic V, Shawber CJ, Reeves C, Shah M, Murtomaki A, Wright J, Herzog T, Tong GX, Kitajewski J. "NOTCH2 expression is decreased in epithelial ovarian cancer and is related to the tumor histological subtype." Pathol Discov. 2013 Aug 16;1:4.
Jovanovic VP, Sauer CM, Shawber CJ, Gomez R, Wang X, Sauer MV, Kitajewski J, Zimmermann RC. "Intraovarian regulation of gonadotropin-dependent folliculogenesis depends on notch receptor signaling pathways not involving Delta-like ligand 4 (Dll4)." Reprod Biol Endocrinol. 2013 May 15;11:43.
Shah MM, Zerlin M, Li BY, Herzog TJ, Kitajewski JK, Wright JD. "The role of Notch and gamma-secretase inhibition in an ovarian cancer model." Anticancer Res. 2013 Mar;33(3):801-8.
Pajvani UB, Shawber CJ, Samuel VT, Birkenfeld AL, Shulman GI, Kitajewski J, Accili D. "Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner." Nat Med. 2011 Jul 31;17(8):961-7.
Park YH, Kim SJ, Jeong BH, Herzog TJ, Wright J, Kitajewski J, Rhim CC, Jang PR, Kang JB, Kim SJ. "Follicular stimulating hormone enhances Notch 1 expression in SK-OV-3 ovarian cancer cells." J Gynecol Oncol. 2010 Jun;21(2):119-24.
Dufraine J, Funahashi Y, Kitajewski J. "Notch signaling regulates tumor angiogenesis by diverse mechanisms." Oncogene. 2008 Sep 1;27(38):5132-7.
Kitamura T, Kitamura YI, Funahashi Y, Shawber CJ, Castrillon DH, Kollipara R, DePinho RA, Kitajewski J, Accili D. "A Foxo/Notch pathway controls myogenic differentiation and fiber type specification." J Clin Invest. 2007 Sep;117(9):2477-85.
Vorontchikhina MA1, Zimmermann RC, Shawber CJ, Tang H, Kitajewski J. "Unique patterns of Notch1, Notch4 and Jagged1 expression in ovarian vessels during folliculogenesis and corpus luteum formation." Gene Expr Patterns. 2005 Jun;5(5):701-9.
