APPLICATIONS OF TECHNOLOGY:

• High-throughput screening for therapeutics that synergize with TIN2 complex disruption
• Sensitizing cancer cells to other therapeutic agents
• Therapy for multiple types of cancer exhibiting p53-negative cancer cells

ADVANTAGES:

• Targets a subset of aggressive cancer cells by using TIN2-complex binding peptides
• Could be combined with conventional chemo- or radiotherapy to increase tumor sensitivity, making it possible to reduce doses and extend treatment times
• Unlike conventional treatments, does not kill normal cells
• Fewer side-effects
• Enhances apoptotic response of cancer cells to chemotherapy
• Enables cost-effective large-scale production of peptides

ABSTRACT:

Judith Campisi, Sahn-Ho Kim, and Seung-Wuk Lee of Lawrence Berkeley National Laboratory have invented a series of TIN2-interface-interacting polypeptides and sequences derived from proteins involved in TIN2 telomeric complexes that target a subset of p53-negative cancer cells, which frequently are metastatic. In human cell-based cultures, these peptides have been shown to selectively disrupt telomeric complexes and kill cancer cells, while sparing normal cells.

Cancer cells generally have short telomeres, making them uniquely sensitive to telomeric complexes. The telomere-associated protein TIN2 binds the telomere DNA-binding proteins TRF1 and TRF2 and the TPP1/POT1 (complex). TIN2 is critical for forming telomere complexes that are essential for telomere structure, telomere length regulation, chromosome end protection and cell fates. It is not yet clear how telomere dysfunction causes cell death in p53-deficient cells, how dysfunctional telomeres are sensed as DNA damage, and the nature of the p53-dependent and p53-independent sensing mechanisms. Nevertheless, telomerase inactivation has been proposed as an anti-cancer strategy because most cancer cells maintain telomere length by expressing this enzyme. Disruption of TIN2-complexes provides a strategy for preferential killing of cancer cells, most of which have short telomeres and lack p53 function.

The Berkeley Lab series of polypeptides may provide a method of selectively eliminating susceptible tumor cells to prevent tumor growth, invasion, or metastasis. They could also be used as a discovery tool in high-throughput screening for therapeutics that could synergize with the disruption of telomeric complexes. In addition, they could be combined with conventional chemo- or radiotherapy to increase tumor sensitivity, making it possible to reduce doses and extend treatment times.

STATUS:

• Patent pending. Available for licensing or collaborative research.

To learn more about licensing a technology from LBNL see http://www.lbl.gov/Tech-Transfer/licensing/index.html.

FOR MORE INFORMATION:

Kim S.H., Davalos A., Heo S.J., Rodier F., Zou Y., Kaminker P., Yannone S., Campisi J. (2008) “Telomere dysfunction and cell survival: Roles for distinct TIN2-containing complexes,” The Journal of Cell Biology 181: 447–460.

REFERENCE NUMBER: IB-2489

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